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Neurology_Adams. Cohen JA, Barkhof F, Comi G, et al; TRANSFORMS Study Group: Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362:402, 2010. Cohen JA, Coles AJ, Arnold DL, et al: Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet 380:1819, 2012. Collongues N, de Seze J: Current and future treatment approaches for neuromyelitis optica. Ther Adv Neurol Disord 4:111, 2011. Compston A, Confavreux C: The distribution of multiple sclerosis. In: Compston A, Lassman H, McDonald I, et al (eds): McAlpine’s Multiple Sclerosis, 4th ed. New York, Churchill Livingstone, 2006, pp 69–112. Compston A, Lassmann H, McDonald I: The history of multiple sclerosis. In: Compston A, Lassman H, McDonald I, et al (eds): McAlpine’s Multiple Sclerosis, 4th ed. New York, Churchill Livingstone, 2006, pp 3–68.


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Neurology_Adams. Livingstone, 2006, pp 3–68. Confavreux C, Hutchinson M, Hours MM, et al: Rate of pregnancy related relapse in multiple sclerosis. N Engl J Med 339:285, 1998. Confavreux C, Suissa S, Saddier P, et al: Vaccinations and the risk of relapse in multiple sclerosis. N Engl J Med 344:319, 2001. Confavreux C, Vukusic S, Moreau T, Adeleine P: Relapses and progression of disability in multiple sclerosis. New Engl J Med 343:1430, 2000. Cook SD, Devereux C, Troiano R, et al: Effect of total lymphoid irradiation in chronic progressive multiple sclerosis. Lancet 1:1405, 1986. Critchley GR, Richardson PL: Vim thalamotomy for the relief of the intention tremor of multiple sclerosis. Br J Neurosurg 12:559, 1998. Dalos NP, Robins PV, Brooks BR, et al: Disease activity and emotional state in multiple sclerosis. Ann Neurol 13:573, 1983. Dean G: The multiple sclerosis problem. Sci Am 233:40, 1970.


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Neurology_Adams. Dalos NP, Robins PV, Brooks BR, et al: Disease activity and emotional state in multiple sclerosis. Ann Neurol 13:573, 1983. Dean G: The multiple sclerosis problem. Sci Am 233:40, 1970. Dean G, Kurtzke JF: On the risk of multiple sclerosis according to age at immigration to South Africa. Br Med J 3:725, 1971. DeJong RN: Multiple sclerosis: History, definition and general considerations. In: Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 9. Amsterdam, North-Holland, 1970, pp 45–62. De Keyser J: Autoimmunity in multiple sclerosis. Neurology 38:371, 1988. Ebers GC: Genetic factors in multiple sclerosis. Neurol Clin 1:645, 1983. Ebers GC: Optic neuritis and multiple sclerosis. Arch Neurol 42:702, 1985. Ebers GC, Bulman DE, Sadovnick AD: A population-based study of multiple sclerosis in twins. N Engl J Med 315:1638, 1986. Ellison PH, Barron KD: Clinical recovery from Schilder’s disease. Neurology 29:244, 1979.


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Neurology_Adams. Ellison PH, Barron KD: Clinical recovery from Schilder’s disease. Neurology 29:244, 1979. European Study Group: Interferon β-1b in secondary progressive MS. Lancet 352:1491, 1998. Fazekas F, Deisenhammer F, Strasser-Fuchs S, et al: Randomised placebo-controlled trial of monthly intravenous immunoglobulin in relapsing-remitting multiple sclerosis. Lancet 349:589, 1997. Fisher RS, Clark AW, Wolinsky JS, et al: Post-infectious leukoencephalitis complicating Mycoplasma pneumoniae infection. Arch Neurol 40:109, 1983. Frohman TC, Galetta S, Fox R, et al: The medial longitudinal fasciculus in ocular motor physiology. Neurol 2008;70:e57–e67. Geny C, Ngeyen JP, Pollin B, et al: Improvement in severe postural cerebellar tremor in multiple sclerosis by thalamic stimulation. Mov Disord 11:489, 1996. Gilbert JJ, Sadler M: Unsuspected multiple sclerosis. Arch Neurol 40:533, 1983.


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Neurology_Adams. Gilbert JJ, Sadler M: Unsuspected multiple sclerosis. Arch Neurol 40:533, 1983. Gold R, Kappos L, Arnold DL, et al: Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis. N Engl J Med; 367:1098, 2012. Goodkin DE, Rudick RA, Medendorp V, et al: Low-dose oral methotrexate in chronic progressive multiple sclerosis. Neurology 47:1153, 1996. Hallett M, Lindsey JW, Adelstein BD, Riley PO: Controlled trial of isoniazid therapy for severe postural cerebellar tremor in multiple sclerosis. Neurology 35:1314, 1985. Halliday AM, McDonald WI: Pathophysiology of demyelinating disease. Br Med Bull 33:21, 1977. Hartung HP, Gonsette R, Konig H, et al: Mitoxantrone in progressive multiple sclerosis: A placebo-controlled, double-blind randomised, multicentre trial. Lancet 360:2018, 2002.


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Neurology_Adams. Hartung HP, Gonsette R, Konig H, et al: Mitoxantrone in progressive multiple sclerosis: A placebo-controlled, double-blind randomised, multicentre trial. Lancet 360:2018, 2002. Hauser SL, Bresnan MJ, Reinherz EL, Weiner HL: Childhood multiple sclerosis: Clinical features and demonstration of changes in T-cell subsets with disease activity. Ann Neurol 11:463, 1982. Hauser SL, Dawson DM, Lehrich JR: Intensive immune suppression in progressive multiple sclerosis: A randomized three arm study of high-dose intravenous cyclophosphamide, plasma exchange and ACTH. N Engl J Med 308:173, 1983. Hauser SA, Waubant E, Arnold DL, et al: B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358:676, 2008. Hely MA, McManis PG, Doran TJ, et al: Acute optic neuritis: A prospective study of risk factors for multiple sclerosis. J Neurol Neurosurg Psychiatry 49:1125, 1986.


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Neurology_Adams. Hely MA, McManis PG, Doran TJ, et al: Acute optic neuritis: A prospective study of risk factors for multiple sclerosis. J Neurol Neurosurg Psychiatry 49:1125, 1986. Hemachudha T, Griffin DE, Giffels JJ, et al: Myelin basic protein as an encephalitogen in encephalomyelitis and polyneuritis following rabies vaccination. N Engl J Med 316:369, 1987. Honkaniemi J, Dastidar P, Kahara V, et al: Delayed MR imaging changes in acute disseminated encephalomyelitis. AJNR Am J Neuroradiol 22:1117, 2001. Hooper J, Whittle IR: Long-term outcome after thalamotomy for movement disorders in multiple sclerosis. Lancet 352:1984, 1998. Howell OW, Reeves CA, Nicholas R, et al: Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 134:2755, 2011. Hynson JL, Kornberg AJ, Coleman LT, et al: Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children. Neurology 56:1308, 2001.


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Neurology_Adams. Hynson JL, Kornberg AJ, Coleman LT, et al: Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children. Neurology 56:1308, 2001. International Multiple Sclerosis Genetics Consortium: Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357:851, 2007. Jacobs L, Kinkel PR, Kinkel WR: Silent brain lesions in patients with isolated idiopathic optic neuritis. Arch Neurol 43:452, 1986. Johnson RT, Griffin DE, Hirsch RL, et al: Measles encephalomyelitis: Clinical and immunologic studies. N Engl J Med 310:137, 1984. Kanter DS, Horensky D, Sperling RA, et al: Plasmapheresis in fulminant acute disseminated encephalomyelitis. Neurology 45:824, 1995. Kappos L, Antel J, Comi G, et al: Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 355:1124, 2006.


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Neurology_Adams. Kappos L, Antel J, Comi G, et al: Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 355:1124, 2006. Kappos L, Li D, Calabresi PA, et al: Ocrelizumab in relapsing-remitting multiple sclerosis: A phase 2, randomised, placebo-controlled multicentre trial. Lancet 378:1779, 2011. Kappos L, Radue EW, O’Connor P, et al; FREEDOMS Study Group: A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362:387, 2010. Katz J, Ropper AH: Progressive necrotic myelopathy: Clinical course in 9 patients. Arch Neurol 57:355, 2000. Kepes JJ: Large focal tumor-like demyelinating lesions of the brain: Intermediate entity between multiple sclerosis and acute disseminated encephalomyelitis: A study of 31 patients. Ann Neurol 33:18, 1993. Kidd D, Burtan B, Plant GT, et al: Chronic relapsing inflammatory optic neuropathy. Brain 126:276, 2003.


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Neurology_Adams. Kidd D, Burtan B, Plant GT, et al: Chronic relapsing inflammatory optic neuropathy. Brain 126:276, 2003. Koelman DL, Chahin S, Mar SS, et al: Acute disseminated encephalomyelitis in 228 patients: A retrospective, multicenter US study. Neurology 31:2085, 2016. Kuhle J, Pohl C, Mehling M, et al: Lack of association between antimyelin antibodies and progression to multiple sclerosis. N Engl J Med 356:371, 2007. Kurland LT: The frequency and geographic distribution of multiple sclerosis as indicated by mortality statistics and morbidity surveys in the United States and Canada. Am J Hyg 55:457, 1952. Kurtzke JF: A reassessment of the distribution of multiple sclerosis. Act Neurol Scand 51:110, 1975. Kurtzke JF, Gudmundsson KR, Bergmann S: Multiple sclerosis in Iceland: I. Evidence of a post-war epidemic. Neurology 32:143, 1982. Kurtzke JF, Hyllested K: Multiple sclerosis in the Faroe Islands: II. Clinical update, transmission, and the nature of MS. Neurology 36:307, 1986.


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Neurology_Adams. Kurtzke JF, Hyllested K: Multiple sclerosis in the Faroe Islands: II. Clinical update, transmission, and the nature of MS. Neurology 36:307, 1986. Lennon VA, Wingerchuk DM, Kryzer TJ, et al: A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet 364:2106, 2004. Lessell S: Corticosteroid treatment of acute optic neuritis. N Engl J Med 326:634, 1992. Lightman S, McDonald WI, Bird AC, et al: Retinal venous sheathing in optic neuritis. Brain 110:405, 1987. Lindå H, von Heijne A, Major EO, et al: Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med 361:1081, 2009. Lublin FD, Cofield SS, Cutter GR, et al: Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol 73:327, 2013. Lucchinetti CF, Brück W, Parisi J, et al: Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann Neurol 47:707, 2000.


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Neurology_Adams. Lucchinetti CF, Brück W, Parisi J, et al: Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann Neurol 47:707, 2000. Lucchinetti CF, Kiers L, O’Duffy A, et al: Risk factors for developing multiple sclerosis after childhood optic neuritis. Neurology 49:1413, 1997. Lucchinetti CF, Mandler RN, McGovern D, et al: A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain 125:1450, 2002. Lucchinetti CF, Popescu BF, Bunyan RF, et al: Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 365:2188, 2011. Mandler RN, Ahmed W, Dencoff JE: Devic’s neuromyelitis optica: A prospective study of seven patients treated with prednisone and azathioprine. Neurology 51:1219, 1998. Mathews WB: Paroxysmal symptoms in multiple sclerosis. J Neuro Neurosurg Psychiat 38:617, 1975.


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Neurology_Adams. Mathews WB: Paroxysmal symptoms in multiple sclerosis. J Neuro Neurosurg Psychiat 38:617, 1975. Mayr WT, Pittock SJ, McClelland RL, et al: Incidence and prevalence of multiple sclerosis in Olmsted County, Minnesota, 1985–2000. Neurology 61:1373, 2003. McAlpine D, Compston MD: Some aspects of the natural history of disseminated sclerosis. Q J Med 21:135, 1952. McAlpine D, Lumsden CE, Acheson ED: Multiple Sclerosis: A Reappraisal, 2nd ed. Edinburgh, UK, Churchill Livingstone, 1972. McDonald WI, Compston A, Edan G, et al: Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121, 2001. Mealy MA, Wingerchuk DM, Palace J, Greenberg BM, Levy M. Comparison of relapse and treatment failure rates among patients with neuromyelitis optica: Multicenter study of treatment efficacy. JAMA Neurol 2014;71:324–330.


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Neurology_Adams. Mendell JR, Kolkin S, Kissel JT, et al: Evidence for central nervous system demyelination in chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 37:1291, 1987. Merle H, Olindo S, Jeannin S, et al: Treatment of optic neuritis by plasma exchange (add-on) in neuromyelitis optica. Arch Ophthalmol 2012;130:858–862. Miller DH, Barkhof F, Frank JA, et al: Measurement of atrophy in multiple sclerosis: Pathological basis, methodological aspects and clinical relevance. Brain 125:1676, 2002. Miller DH, Khan OA, Sheremata WA, et al: A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348:15, 2003. Moulin D, Paty DW, Ebers GC: The predictive value of CSF electrophoresis in “possible” multiple sclerosis. Brain 106:809, 1983. Munger KL, Levin LI, Hollis BW, et al: Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296:2832, 2006.


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Neurology_Adams. Munger KL, Levin LI, Hollis BW, et al: Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296:2832, 2006. Narisco P, Galgani S, Del Grosso B, et al: Acute disseminated encephalomyelitis as manifestation of primary HIV infection. Neurology 57:1493, 2001. National Center for Health Statistics, Collins JG: Types of Injuries and Impairments due to Injuries. United States Vital Statistics. Series 10, no 159, DHHS, no (PHS) 871587. Washington, DC, U.S. Public Health Service, 1986. O’Connor P, Wolinsky JS, Confavreux C, et al; TEMSO Trial Group: Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 365:1293, 2011. Optic Neuritis Study Group: The five-year risk of MS after optic neuritis. Neurology 49:1404, 1997. Ormerod IEC, McDonald WI, DuBoulay GH, et al: Disseminated lesions at presentation in patients with optic neuritis. J Neurol Neurosurg Psychiatry 49:124, 1986.


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Neurology_Adams. Ormerod IEC, McDonald WI, DuBoulay GH, et al: Disseminated lesions at presentation in patients with optic neuritis. J Neurol Neurosurg Psychiatry 49:124, 1986. Osterman PO, Westerberg CE: Paroxysmal attacks in multiple sclerosis. Brain 98:189, 1975. Padovan CS, Bise K, Hahn J, et al: Angiitis of the central nervous system after allogenic bone marrow transplantation? Stroke 30:1651, 1999. Pandit L, Asgari N, Apiwattanakul M, et al. Demographic and clinical features of neuromyelitis optica: A review. Multiple Sclerosis 21:845, 2015. Percy AK, Nobrega FT, Okazaki H: Multiple sclerosis in Rochester, Minnesota: A 60-year appraisal. Arch Neurol 25:105, 1971. Pittock SJ, Lennon VA, de Seze J, et al: Neuromyelitis optica and non organ-specific autoimmunity. Arch Neurol 65:78, 2008. Pittock SJ, Mayr WT, McClelland RL, et al: Disability profile of MS did not change over 10 years in a population-based prevalence cohort. Neurology 62:601, 2004.


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Neurology_Adams. Pittock SJ, Mayr WT, McClelland RL, et al: Disability profile of MS did not change over 10 years in a population-based prevalence cohort. Neurology 62:601, 2004. Pittock SJ, Weinshenker BG, Lucchinetti CF, et al: Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol 63:964, 2006. Polman CH, O’Connor PW, Havardova E, et al: A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354:899, 2006. Polman CH, Reingold SC, Banwell B, et al: Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69:292, 2011. Poser CM: Exacerbations, activity and progression in multiple sclerosis. Arch Neurol 37:471, 1980. Poser CM, Goutieres F, Carpentier M: Schilder’s myelinoclastic diffuse sclerosis. Pediatrics 77:107, 1986. Poskanzer DC, Schapira K, Miller H: Multiple sclerosis and poliomyelitis. Lancet 2:917, 1963.


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Neurology_Adams. Alvord EC Jr (eds): “Allergic” Encephalomyelitis. Springfield, IL, Charles C Thomas, 1959, pp 58–129. Sibley WA, Bamford CRF, Clark K, et al: A prospective study of physical trauma and multiple sclerosis. J Neurol Neurosurg Psychiatry 54:584, 1991. Slamovitis S, Rosen CE, Cheng KP, et al: Visual recovery in patients with optic neuritis and visual loss to no light perception. Am J Ophthalmol 111:209, 1991. Stricker RD, Miller RG, Kiprov DO: Role of plasmapheresis in acute disseminated (postinfectious) encephalomyelitis. J Clin Apher 7:173, 1992. Thomas PK, Walker RWH, Rudge P, et al: Chronic demyelinating peripheral neuropathy associated with multifocal central nervous system demyelination. Brain 110:53, 1987. Thompson AJ, Polman CH, Miller DH, et al: Primary progressive multiple sclerosis. Brain 120:1085, 1997. Thygessen P: The Course of Disseminated Sclerosis: A Close-Up of 105 Attacks. Copenhagen, Rosenkilde and Bagger, 1953.


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Neurology_Adams. Thygessen P: The Course of Disseminated Sclerosis: A Close-Up of 105 Attacks. Copenhagen, Rosenkilde and Bagger, 1953. Tippett DS, Fishman PS, Panitch HS: Relapsing transverse myelitis. Neurology 41:703, 1991. Tourtellotte WW, Booe IM: Multiple sclerosis: The blood-brain barrier and the measurement of de novo central nervous system IgG synthesis. Neurology 28(Suppl):76, 1978. Tradtrantip L, Zhang H, Saadoun S, et al: Anti-aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica. Ann Neurol 71:314, 2014. Tremlett H, Paty D, Devonshire V; Disability progression in multiple sclerosis is slower than previously reported. Neurology 66:172, 2006. van der Mei IA, Ponsonby AL, Dwyer T, et al: Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia. J Neurol 254:581, 2007. Vermersch F, Kappos L, Gold R, et al: Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy. Neurology 76:1697, 2011.


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Neurology_Adams. Tasmania, Australia. J Neurol 254:581, 2007. Vermersch F, Kappos L, Gold R, et al: Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy. Neurology 76:1697, 2011. Vrethem M, Mattsson E, Hebelka H, et al: Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid. Mult Scler 9:239, 2003. Waksman BH, Adams RD: Studies of the effect of the Schwartzman reaction on the lesions of experimental allergic encephalomyelitis. Am J Pathol 33:131, 1957. Weinshenker BG, O’Brien PC, Petterson TM, et al: A randomized trial of plasma exchange in acute central nervous system demyelinating inflammatory disease. Ann Neurol 46:878, 1999. Weinshenker BG, Rice GP, Noseworthy JH, et al: The natural history of multiple sclerosis: A geographically based study: 2. Predictive value of the early clinical course. Brain 112:1419, 1989.


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Neurology_Adams. Weinshenker BG, Rice GP, Noseworthy JH, et al: The natural history of multiple sclerosis: A geographically based study: 2. Predictive value of the early clinical course. Brain 112:1419, 1989. Wenning W, Haghikia A, Laubenberger J, et al: Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N Engl J Med 361:1075, 2009. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85:177, 2015. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol 6:805, 2007. Wingerchuk DM, Lennon VA, Pittock SJ, et al: Revised diagnostic criteria for neuromyelitis optica. Neurology 66:1485, 2006. Zivadinov R, Rudick RA, De Masi R, et al: Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology 57:1239, 2001.


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Neurology_Adams. Zivadinov R, Rudick RA, De Masi R, et al: Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology 57:1239, 2001. Figure 35-1. MRI in multiple sclerosis. Upper left, axial T2-FLAIR image showing multiple discrete periventricular hyperintense plaques, as well as two subcortical plaques in the right frontal and parietal lobes. Upper right, coronal T1-post gadolinium image showing abnormal enhancement of the right optic nerve in a case of acute optic neuritis (arrow). Lower left, sagittal T2-FLAIR image showing two hyperintense plaques emanating radially from the body of the corpus callosum (“Dawson fingers”). Lower right, sagittal T2 MRI showing multiple discrete hyperintense plaques within the cervical spinal cord. The lesion at C3 is acute with accompanying expansion of the cord. The lesion at the T1 level of the cord is chronic and shows cord atrophy.


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Neurology_Adams. Figure 35-2. Left Axial T2-FLAIR image of a tumefactive MS lesion in the left temporal lobe. Right T1-post gadolinium showing an “open ring” of abnormal contrast enhancement, a common imaging feature of acute demyelinating plaques that is less typical of tumors or abscesses. Figure 35-3. MRI of the spinal cord in neuromyelitis optica. Sagittal T2 image showing a hyperintense, longitudinally extensive, confluent cervico-thoracic lesion. Figure 35-4. Acute (postinfectious) disseminated encephalomyelitis (ADEM). Axial T2-FLAIR images showing left inferior frontal (left) and right anterior temporal (right) edematous lesions. Figure 35-5. Acute necrotizing hemorrhagic leukoencephalitis. Axial T2-FLAIR MRI shows extensive abnormal hyperintensity throughout the hemispheric white matter as well as within the deep gray nuclei. Additional signal abnormality in the cortical sulci is due to subarachnoid hemorrhage.


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Neurology_Adams. Figure 35-6. Abnormal T2 hyperintensity in the splenium of the corpus callosum in a patient with graft-versus-host disease 2 years following allogenic bone marrow transplantation. Inherited Metabolic Diseases of the Nervous System


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Neurology_Adams. Inherited Metabolic Diseases of the Nervous System Advances in biochemistry and molecular genetics have led to the discovery of such a large number of metabolic diseases of the nervous system that it taxes the mind just to remember their names. As the causes and mechanisms of the diseases included in this chapter are increasingly being expressed in terms of molecular genetics, it seems appropriate, by way of introduction, to consider briefly some basic facts pertaining to the genetics of neurologic disease. The reader is referred to the continuously updated database, Online Mendelian Inheritance in Man (OMIM)(http://www.ncbi.nlm.nih.gov/omim). This resource contains an overview on all known mendelian disorders and over 15,000 genes. It can be used to cross reference disorders, genes, and even single symptoms and the associated genetic variants.


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Neurology_Adams. The brain is more frequently affected by a genetic abnormality than any other organ, probably because of the large number of genes implicated in its development (an estimated one-third of the human genome). Approximately one-third of all inherited diseases are neurologic in some respect; if one adds the inherited diseases affecting the musculature, skeleton, eye, and ear, the number rises to 80 to 90 percent. Approximately 7 percent of diseases in hospitalized children are estimated to be attributable to single-gene defects and 0.4 to 2.5 percent to a chromosomal abnormality. Another 22 to 31 percent have a disease putatively due to polymorphisms, most of which are yet to be specified. Mitochondrial inheritance of mutations is much less frequent but gives rise to several distinctive diseases.


Neurology_Adams

Neurology_Adams. Although only a minority of inherited diseases is identified as an enzymopathy, this group represents the most direct translation of mendelian disorders to primary defects in proteins. These constitute only one-third of the known recessive (autosomal and X-linked) disorders. Most enzymopathies become manifest in infancy and childhood; only a few appear as late as adolescence or adult life. Many damage the nervous system so severely that survival to adult years and reproduction are impossible, and some cause death in utero. As a group, these diseases—along with congenital anomalies (see Chap. 37), birth injuries, epilepsy, disharmonies of development, and learning disabilities (see Chap. 27)—make up the bulk of the clinical problems with which the pediatric neurologist must contend.


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Neurology_Adams. The diseases grouped in this chapter, and many in the next, represent four particular categories of genetic abnormality: (1) monogenic disorders determined by a single mutation that follow a mendelian pattern of inheritance. These mutations can be of a single base pair (point mutation), an insertion or deletion of nucleotides, or structural rearrangements of a sequence of DNA, such as translocations or inversions; because the most important of these involve the protein coding (exonic) portion of DNA, they are likely to disrupt the structure and function of enzymes or cellular structural proteins; this “exome” constitutes 1 percent of the entire genome; (2) a type of monogenic mutation characterized by duplications or deletions of genes or parts of chromosomes, termed copy number variations; these account for some proportion the heritability of common diseases; (3) single nucleotide polymorphisms, which are variations from the most common, “wild type,” sequence of a gene and are by


Neurology_Adams

Neurology_Adams. these account for some proportion the heritability of common diseases; (3) single nucleotide polymorphisms, which are variations from the most common, “wild type,” sequence of a gene and are by convention present with a frequency of greater than 1 percent in the population; these play a role in the genesis of disease but do not obligatorily result in a somatic aberration or alternatively, they interact with exogenous environmental factors; and (4) mitochondrial gene mutations that are inherited in a nonmendelian, mainly maternally inherited pattern. Furthermore, the expression of certain diseases may be modulated by epigenetic alterations in gene expression, which have not been fully explored.


Neurology_Adams

Neurology_Adams. Genetic analysis of disease has advanced from early approaches of linking sites on chromosomes to a disorder, to genome-wide array analysis (GWAS), which matches genetic variants to a large number of persons with a trait, a method of identifying candidate variations in the genome, to exome sequencing, studying the 1 percent of the genome that is expressed, which is effective in determining the genetic variants associated with rare mendelian disorders that are present in a small number of individuals. A summary of the uses of whole exome sequencing for the diagnosis of rare inherited disorders is given by Yang and colleagues. They were able to identify a disorder in one-quarter of their cohort of 250 patients, including common and rare conditions, some of which were neurologic.


Neurology_Adams

Neurology_Adams. Traditionally, the recognition of the broad categories of genetically determined diseases has rested on their pattern of occurrence in families, segregated according to mendelian inheritance into autosomal dominant, autosomal recessive, and sex-linked types. As mentioned, mutations of nuclear DNA account for the heritable autosomal and sex-linked diseases described in this chapter, and they are remarkably diverse in nature. Some are lethal and are therefore not transmitted to successive generations; others are less harmful and may conform to one of the classic mendelian patterns. The mutation may be large and result in duplication of a major part of a chromosome or even of the entire gene (diploidy or triploidy) or a deletion (haploidy). Other mutations are quite small, involving only a single base pair (“point mutation”). Between these two extremes are deletions or duplications that include a portion of a gene, an entire gene, or contiguous genes, as mentioned above.


Neurology_Adams

Neurology_Adams. The factors conducive to mutations are poorly understood. The parent’s increasing age is important in relation to some mutations; the size, structure, and placement of the gene on the chromosome are important in others. A mutation of the DNA of a germ cell leaves unchanged the somatic phenotype of the individual in whom it occurs, but it may have a devastating effect on the descendants. Conversely, a DNA mutation of a somatic cell affecting only part of the cell population may change the individual harboring it but is not passed on to the descendants. Such an individual, with both normal cells and cells containing the mutant gene, is referred to as a mosaic. Mutations of somatic cells appear to be most pertinent to cancer and aging.


Neurology_Adams

Neurology_Adams. In the monogenic inheritance of all three mendelian patterns, the mutation usually causes an abnormality of a single protein. It may involve an enzyme, peptide hormone, immunoglobulin, collagen, membrane channel, or coagulation factor. Such abnormalities of single genes have been isolated in several hundred diseases, but less is known of their protein products. About one-quarter of these diseases are apparent soon after birth and more than 90 percent by puberty. More than half of them affect more than one organ. Of the 10 in every 1,000 live births with monogenic diseases, 7 are dominant, 2.5 are recessive, and the remainder are sex linked.


Neurology_Adams

Neurology_Adams. Autosomal dominant mutations usually cause manifest disease in heterozygotes, but variations in the size of the gene abnormality can produce any one of several phenotypes. This poses a challenge to the current clinical and pathologic classifications of disease. Moreover, an identical clinical syndrome may be traced to a gene on two different chromosomes. Even more surprising, an estimated 28 percent of all gene loci have polymorphic rather than monomorphic effects—that is, the same mutation has several different phenotypic expressions. Another problem is that of differentiating dominant from recessive inheritance. In small families, in which only one descendant is afflicted and the parent is seemingly normal, one may mistakenly conclude that the inheritance is recessive. Other characteristics of mutational diseases are penetrance, a measure of the proportion of individuals with a given genotype who will show the phenotype, and expressivity, referring to the severity of disease in an


Neurology_Adams

Neurology_Adams. of mutational diseases are penetrance, a measure of the proportion of individuals with a given genotype who will show the phenotype, and expressivity, referring to the severity of disease in an affected individual. Variable degrees of penetrance and expressivity are characteristic features of dominant patterns of inheritance but not of recessive ones. There is also a general tendency for dominantly inherited disease to first appear long after birth.


Neurology_Adams

Neurology_Adams. Autosomal recessive forms of inherited metabolic diseases, in contrast to dominant ones, occur only in the homozygous state (both alleles are abnormal). They are usually characterized by an onset soon after birth. The basic abnormality in the recessively inherited diseases discussed in this chapter is more often an enzyme deficiency than an abnormality of some other protein.


Neurology_Adams

Neurology_Adams. In disorders of X-linked genes, in which the mutant gene affects mainly one sex, the female will suffer the same fate as the male if one X chromosome has been inactivated, as happens in most cells during embryonic development (the Lyon phenomenon). However, even if the abnormal X chromosome is not widely expressed, the female carrier may still exhibit minor abnormalities. In the latter case, sex-linked inheritance becomes difficult to distinguish from dominant inheritance. Also, sex linkage is deceptive when a disease is lethal to one sex. In contrast to autosomal recessive mutations, the abnormality has more often been one of a basic protein than an enzyme deficiency.


Neurology_Adams

Neurology_Adams. Multifactorial genetic diseases may also be familial. They may present as constitutional disorders with gene abnormalities located on several chromosomes (polygenic, or “complex genetics”) or may arise from single nucleotide polymorphisms or copy number variations. Here, the relative contributions of genetic and environmental influences are highly variable. The occurrence of many disorders that display high degrees of familial incidence, such as schizophrenia and Gilles de la Tourette syndrome, but do not strictly conform to classic genetic principles has been attributed to this type of complex genetics. The separation of metabolic-genetic from degenerative diseases (accorded a separate chapter) may disquiet the reader, for there are many overlaps between the two groups. The current division is tenable only until such time as all the degenerative diseases will have been shown to have a comprehensible pathogenesis. The Genetics of Mitochondrial Disease


Neurology_Adams

Neurology_Adams. The Genetics of Mitochondrial Disease An entirely different type of genetic transmission relating to the DNA that lies in the mitochondria has been elucidated. Mitochondria contain their own extrachromosomal DNA, distinct from nuclear DNA. Mitochondrial DNA (“the other human genome”) is a double-stranded, circular molecule that encodes the protein subunits required mainly for translation of the proteins located on the mitochondrial inner membrane. Of the 37 mitochondrial genes, small in number by comparison with nuclear DNA, 13 partake in the cellular processes of oxidative phosphorylation and the production of adenosine triphosphate (ATP). A few genes in the cell’s nucleus also code for a considerable number of oxidative enzymes of the mitochondria, but their inheritance follows a mendelian pattern; consequently, a mitochondrial disorder may fail to display maternal inheritance that is characteristic of mitochondrial mutations as described below.


Neurology_Adams

Neurology_Adams. Each mitochondrion contains up to 10 ringed DNA molecules, and each cell, of course, contains numerous mitochondria. In the cell, mitochondria with mutant genes may exist next to normal mitochondria (heteroplasmy), a state that permits an otherwise lethal mutation to persist (Johns). The presence of either completely normal or completely mutant mitochondrial DNA is termed homoplasmy. The essential feature of mitochondrial genes and the mutations to which they are subject is that they are inherited almost exclusively through maternal lineage. This is explained by the transmission of virtually all mitochondria from the ovum at the time of conception. Moreover, mitochondrial DNA does not recombine, thus permitting the accumulation of mutations through maternal lines. Also, the replication and distribution of mitochondrial DNA during cell division do not follow the nuclear mitotic cycle. Instead, there are contributions during cell division from the genes of various mitochondria to the


Neurology_Adams

Neurology_Adams. and distribution of mitochondrial DNA during cell division do not follow the nuclear mitotic cycle. Instead, there are contributions during cell division from the genes of various mitochondria to the progeny of dividing cells. The combination of a heteroplasmic state and the capricious dispersion of mitochondria to daughter cells (replicative segregation) explains the variable expression of mitochondrial mutations in different tissues and in different regions of the nervous system.


Neurology_Adams

Neurology_Adams. The genetic error in each of the mitochondrial diseases is most often a single-point mutation that leads to the alteration of a single amino acid, but there are also single or multiple deletions or duplications of mitochondrial genes that do not conform to maternal inheritance because they are caused by nuclear DNA defects. It is important to note that approximately 85 percent of the protein components of the respiratory chain are coded in nuclear DNA and are then imported into the mitochondrion; as mentioned above, this allows for a mitochondrial disease with a mendelian pattern of inheritance rather than a maternal one. Another of the general rules of mitochondrial inheritance is exemplified by an infantile myopathy (cytochrome oxidase deficiency) that is usually fatal but may also occur in a less severe form and have a later onset. In cases of earlier onset, there is less of the normal mitochondrial DNA than in the cases of later onset.


Neurology_Adams

Neurology_Adams. Because the unique function of mitochondria is the production of ATP by oxidative phosphorylation, it is not surprising that many of the genes contained in mitochondria code for proteins in the respiratory chain. However, there is not always concordance between the error in the mitochondrial genome and the enzymatic defect that leads to disease. Of the five complexes that make up the respiratory chain, cytochrome-c oxidase (complex IV) is the one most often disordered, and its deficient function gives rise to lactic acidosis, a feature common to many of the mitochondrial disorders (see further on). In keeping with the mutable nature of this class of disorders, it is thought that some cases of complex IV defect are autosomally transmitted. Complex I defects, which originate in mitochondrial mutations, are seen, for example, in Leber optic atrophy. A more complete account of the disorders of the mitochondrial respiratory chain can be found in the review by Leonard and Schapira.


Neurology_Adams

Neurology_Adams. As one would expect, aberrant function of the ubiquitous energy-producing mitochondria results in disease of many organs besides skeletal muscle (e.g., diabetes and other endocrinopathies and minor dysmorphic features are seen in several mitochondrial disorders). Nevertheless, most of the mitochondrial disorders affect the nervous system prominently and at times exclusively. Two characteristics traceable to mitochondrial abnormalities are particularly common: one is a special change in muscle fibers termed ragged red fibers, a clumping of mitochondria in muscle fibers described in more detail further on, and the other is a systemic lactic acidosis. Other than these, each of the mitochondrial diseases has distinctive features and in their main elements they do not resemble each other. The main syndromes are MELAS and MERRF (acronyms defined further on), Leber hereditary optic atrophy, progressive external ophthalmoplegia, and the Leigh syndrome. These diseases are described in detail


Neurology_Adams

Neurology_Adams. main syndromes are MELAS and MERRF (acronyms defined further on), Leber hereditary optic atrophy, progressive external ophthalmoplegia, and the Leigh syndrome. These diseases are described in detail in the last part of this chapter.


Neurology_Adams

Neurology_Adams. Diagnostic Features of Hereditary Metabolic Diseases In clinical practice, one should consider the possibility of a hereditary metabolic disease when presented with the following lines of evidence: 1. A neurologic disorder of similar type in a sibling or close relative 2. Recurrent nonconvulsive episodes of impaired consciousness or intractable seizures in infants or young children or infantile spasms and progressive myoclonic seizures in the absence of neonatal hypoxia-ischemia 3. Some combination of unexplained symmetrical or generalized spastic weakness, cerebellar ataxia, extrapyramidal disorder, deafness, or blindness 4. Progression of a neurologic disease measured in months, or a few years, sometimes identified by achieving and then losing developmental milestones, as outlined in Chap. 27 5. Developmental delay in an individual if there are no congenital somatic abnormalities or developmental delay in a sibling or close relative


Neurology_Adams

Neurology_Adams. In the face of such clinical information, one should obtain appropriate biochemical analyses of blood, urine, and cerebrospinal fluid (CSF); MRI of the brain; and genetic studies.


Neurology_Adams

Neurology_Adams. In addition to the investigation of symptomatic individuals, the array of available genetic and biochemical tests has made practical the mass screening of newborns for inborn metabolic defects. Innovative tests have also led to the discovery of a number of previously unknown diseases and have clarified the basic biochemistry of old ones. As a consequence, the neurologist’s role is changing. No longer must we wait until a disease of the nervous system has declared itself by conventional symptoms and signs, by which time the underlying lesion may have become irreversible. Now it is possible to find patients who, although asymptomatic, are at risk and to introduce dietary and other measures that may prevent injury to the nervous system. This is especially important to families who have already had an affected infant. To assume this new responsibility intelligently requires knowledge of genetics, biochemical screening methods, and public health measures.


Neurology_Adams

Neurology_Adams. The many clinical syndromes by which these inborn errors of metabolism declare themselves vary in accordance with the nature of the biochemical defect and the stage of maturation of the nervous system at which these metabolic alterations become apparent. In phenylketonuria, for example, there is a specific effect on the cerebral white matter, mainly during the period of active myelination; once the stages of myelinogenesis are complete as detailed in Chap. 27, the biochemical abnormality becomes relatively harmless. Even more important from the neurologist’s point of view is the level of function that has been achieved by the developing nervous system when the disease strikes. A derangement of function in a neonate or infant, in whom much of the cerebrum is not fully developed, is much less obvious than one in an older child. Moreover, as the disease evolves, the clinical manifestations are always influenced by the ongoing maturation of the untouched elements in the nervous system.


Neurology_Adams

Neurology_Adams. less obvious than one in an older child. Moreover, as the disease evolves, the clinical manifestations are always influenced by the ongoing maturation of the untouched elements in the nervous system. These interactions may give the impression of regression of attained neurologic function, lack of progress of development (developmental delay), or even improvement in function that is attributable to continuing maturation of the normal parts of the nervous system.


Neurology_Adams

Neurology_Adams. Because of the overriding importance of the age factor and the tendency of certain pathologic processes to appear in particular epochs of life, it has seemed to the authors logical to group the inherited metabolic diseases not according to their major syndromes of expression, as we have done in other parts of the book, but in relation to the periods of life at which they are most likely to be encountered: the neonatal period, infancy (1 to 12 months), early childhood (1 to 4 years), late childhood, adolescence, and adult life. Only in the last two age periods do we return to the more clinically useful syndromic ordering of diseases. In adopting this chronological subdivision, we realize that certain hereditary metabolic defects that most typically manifest themselves at a particular period in life are not necessarily confined to that epoch and may appear, sometimes in variant form, at a later age. Such variations are noted at appropriate points in the discussion.


Neurology_Adams

Neurology_Adams. A small number of progressive metabolic diseases become evident in the first few days of life. The importance of these diseases relates not to their frequency (they constitute only a small fraction of diseases that compromise nervous system function in the neonate) but to the fact that they must be recognized promptly if the infant is to be prevented from dying or from suffering a lifelong severe developmental delay. This inherent threat introduces an element of urgency into neonatal neurology. Recognition of these diseases is also important for purposes of family and prenatal testing.


Neurology_Adams

Neurology_Adams. Two approaches to the neonatal metabolic disorders are possible—one, to screen every newborn, using a battery of biochemical tests of blood and urine, and the other, to undertake in the days following birth a detailed neurologic assessment that will detect the earliest signs of these diseases. Unfortunately, not all the biochemical tests have been simplified to the point where they can be adapted to a mass screening program, and many of the commonly used clinical tests at this age have yet to be validated as markers of disease. Moreover, many of the biochemical tests are costly, and practical issues, such as cost-effectiveness, insinuate themselves, to the distress of the pediatrician. The introduction of tandem mass spectrometry for the evaluation of blood and urine has allayed some of the latter concerns. The extent of screening varies across countries. In the U.S. screening includes several disorders relevant to neurologic development including the categories of endocrine


Neurology_Adams

Neurology_Adams. some of the latter concerns. The extent of screening varies across countries. In the U.S. screening includes several disorders relevant to neurologic development including the categories of endocrine (particularly hypothyroidism), amino acid, organic acid, fatty acid, mucopolysaccharide, and other disorders. A hearing screening test is also usually mandatory before an infant is discharged. These tests are organized and operated at the state level.


Neurology_Adams

Neurology_Adams. Neurologic Assessment of Neonates With Metabolic Disease


Neurology_Adams

Neurology_Adams. As pointed out in Chap. 27, the neonate’s nervous system functions essentially at a brainstem–spinal level. The pallidum and visuomotor cortices are only beginning to be myelinated and their contribution to the totality of neonatal behavior cannot be very great. Neurologic examination, to be informative, must therefore be directed to evaluating diencephalic–midbrain, cerebellar–lower brainstem, and spinal functions. The integrity of these functions in the neonate is most reliably assessed by noting the following, as was described in Chap. 27: 1. Control of respiration and body temperature; regulation of thirst, fluid balance, and appetite–hypothalamus–brainstem mechanisms 2. Certain elemental automatisms, such as sucking, rooting, swallowing, grasping—brainstem–cerebellar mechanisms 3. Movements and postures of the neck, trunk, and limbs, such as reactions of support, extension of the neck and trunk, flexion movements, and steppage—lower brainstem (reticulospinal), cerebellar, and


Neurology_Adams

Neurology_Adams. and postures of the neck, trunk, and limbs, such as reactions of support, extension of the neck and trunk, flexion movements, and steppage—lower brainstem (reticulospinal), cerebellar, and spinal mechanisms 4. Muscle tone of limbs and trunk—spinal neuronal and neuromuscular function 5. Reflex eye movements—tegmental midbrain and pontine mechanisms (a modified optokinetic nystagmus can be recognized by the third day of life) 6. The state of alertness and attention (stimulus responsivity and capacity of the examiner to make contact) as well as sleep–waking and electroencephalographic patterns—mesencephalic–diencephalic mechanisms 7. Certain reflexive reactions such as the startle (Moro) response and placing reactions of the foot and hand—upper brainstem–spinal mechanisms with possible cortical facilitation


Neurology_Adams

Neurology_Adams. Derangements of these functions are manifest as impairments of alertness and arousal, hypotonia, disturbances of ocular movement (oscillations of the eyes, nystagmus, loss of tonic conjugate deviation of the eyes in response to vestibular stimulation, i.e., to rotation of the upright infant), failure to feed, tremors, clonic jerkings, tonic spasms, opisthotonos, diminution or absence of limb movements, irregular or chaotic breathing, hypothermia or poikilothermia, bradycardia, circulatory difficulties, poor color, and seizures.


Neurology_Adams

Neurology_Adams. In most instances of neonatal metabolic disease, the pregnancy and delivery proceed without mishap. Birth at full term is usual. The infant is of a size and weight expected for the duration of pregnancy, and there are no signs of a developmental abnormality (in a few instances the infant is somewhat small, and in GM1 gangliosidosis there may be a pseudo-Hurler appearance; see further on). Furthermore, function continues to be normal in the first few days of life. The first hint of trouble may be the occurrence of feeding difficulties: food intolerance, diarrhea, and vomiting. The infant becomes fretful and fails to gain weight and thrive—all of which should suggest a disorder of amino acid, ammonia, or organic acid metabolism.


Neurology_Adams

Neurology_Adams. The first definite indication of disordered nervous system function is likely to be the occurrence of seizures. These usually take the form of unpatterned clonic or tonic contractions of one side of the body or independent bilateral contractions, sudden arrest of respiration, turning of the head and eyes to one side, or twitching of the hands and face. Some of the ill-formed seizures may become generalized. They occur singly or in clusters and, in the latter instance, are associated with unresponsiveness, immobility, and arrest of respiration.


Neurology_Adams

Neurology_Adams. The other clinical abnormalities in the motor realm, according to authorities such as Prechtl and Beintema, can be subdivided roughly into three groups, each of which constitutes a kind of syndrome: (1) hyperkinetic–hypertonic, (2) apathetic–hypotonic, or (3) unilateral or hemisyndromic. Prechtl and Beintema, from a study of more than 1,500 newborns, found that if clinical examination consistently discloses any one of the 3 syndromes, the chances are 2 in 3 that by the seventh year the child will be manifestly abnormal neurologically. They found also that certain neurologic signs—such as facial palsy, lack of grasping, excessive floppiness, and impairment of sucking—while sometimes indicative of serious disease of the nervous system, are less dependable; also, being rare, these signs will identify but few brain-damaged infants. It is not the single neurologic sign but groups of them that are held to be the most reliable indices of brain abnormality, and the 3 syndromes mentioned above


Neurology_Adams

Neurology_Adams. identify but few brain-damaged infants. It is not the single neurologic sign but groups of them that are held to be the most reliable indices of brain abnormality, and the 3 syndromes mentioned above are the important ones, even though their anatomic and physiologic bases are not completely known.


Neurology_Adams

Neurology_Adams. In cases of hypocalcemia–hypomagnesemia, the hyperkinetic–hypertonic syndrome prevails. Although most of the other diseases tend to induce the apathetic–hypotonic state, the hyperactive–hypertonic syndrome may represent the initial phase of the illness and always carries a less ominous prognosis than the apathetic– hypotonic state, which represents a more severe condition regardless of cause. The third putative group of unilateral abnormalities in the metabolic diseases is less common and more difficult to recognize. These syndromes frequently overlap and seizures may occur in all of them. The anatomic correlate for some of these neurologic abnormalities can be observed by MRI. Clearly what is needed is a more definitive neonatal neurologic semiology utilizing numerous stimulus–response tests, including those described by Andre Thomas and Dargassis.


Neurology_Adams

Neurology_Adams. In New England, screening of all newborns for metabolic disorders has been practiced for almost 50 years. Data on the diseases with neurologic implications were in the past collated by our colleague, H.L. Levy of Boston Children’s Hospital, and are summarized in Table 36-1. In the past, some of these were identified by colorometric chemical tests of urine (Table 36-2). This has been largely replaced by tandem mass spectroscopy. To this group should be added the inherited hyperammonemic syndromes and vitamin-responsive aminoacidopathies (such as pyridoxine dependency and biopterin deficiency), as well as certain nonfamilial metabolic disorders that make their appearance in the neonatal period—hypocalcemia, hypothyroidism and cretinism, hypomagnesemia with tetany, and hypoglycemia.


Neurology_Adams

Neurology_Adams. It is important to note that the three most frequently identified hereditary metabolic diseases—phenylketonuria (PKU), hyperphenylalaninemia, and congenital hypothyroidism—do not become clinically manifest in the neonatal period and are therefore discussed in a later portion of this chapter and in Chap. 39 (in the discussion of congenital hypothyroidism). This is fortunate, for it allows time to introduce preventive measures before the first symptoms appear. A number of other metabolic disorders, which can be recognized either by screening or by early signs, are synopsized below. Included under this heading is a group of diseases that respond not to dietary restriction of a specific amino acid but to the oral supplementation of a specific vitamin. Some 30 vitamin-responsive aminoacidopathies are known (they are all rare, but the more frequent ones are listed in Table 40-3), and many of them result in injury to the central nervous system (CNS).


Neurology_Adams

Neurology_Adams. Pyridoxine-dependent seizures Pyridoxine dependency is the prototypic example of a genetic, vitamin-dependent biochemical disorder, albeit a rare disease. It is inherited as an autosomal recessive trait and is characterized by the early onset of convulsions, sometimes occurring in utero; failure to thrive; hypertonia–hyperkinesia; irritability; tremulous movements (“jittery baby”); exaggerated auditory startle (hyperacusis); and later, if untreated, by psychomotor retardation. The specific laboratory abnormality is an increased excretion of xanthurenic acid in response to a tryptophan load. There are decreased levels of pyridoxal-5-phosphate and gamma-aminobutyric acid (GABA) in brain tissue. The mutation is of the ALDH7A1 gene.


Neurology_Adams

Neurology_Adams. The neuropathology has been studied in only a few cases. One patient of our colleague R.D. Adams, a 13.5-year-old boy affected in the neonatal period, was left in a state of mental retardation, with pale optic discs and spastic legs; the brain weight was 350 g below normal. There was a decreased amount of central white matter in the cerebral hemispheres and a depletion of neurons in the thalamic nuclei and cerebellum, with gliosis (Lott et al). Most importantly, in pyridoxine deficiency, the administration of 50 to 100 mg of vitamin B6 suppresses the seizure state, and daily doses of 40 mg permit normal development.


Neurology_Adams

Neurology_Adams. Some patients with increased concentrations of serum phenylalanine in the neonatal period are unresponsive to measures that lower phenylalanine. They are usually found to have a defect in biopterin metabolism. The defect is usually the result of a mutation in tetrahydrobiopterin or BH4. If this condition is unrecognized and not treated promptly, it leads to seizures of both myoclonic and, later, grand mal types, combined with a poor level of responsiveness and generalized hypotonia. Swallowing difficulty is another prominent symptom. Within a few months, developmental delay becomes prominent. Unlike in PKU, phenylalanine hydroxylase enzyme levels are normal, but there is a lack of tetrahydrobiopterin, which is a cofactor of phenylalanine hydroxylase. Treatment consists of administration of tetrahydrobiopterin in a dosage of 7.5 mg/kg/d in combination with a low-phenylalanine diet. It is important to recognize this condition early in life by the measurement of urine pterins and to


Neurology_Adams

Neurology_Adams. of tetrahydrobiopterin in a dosage of 7.5 mg/kg/d in combination with a low-phenylalanine diet. It is important to recognize this condition early in life by the measurement of urine pterins and to institute appropriate therapy before irreversible brain injury occurs. A later onset form with diurnally fluctuating dystonia has also been described but its nature is not certain.


Neurology_Adams

Neurology_Adams. Inheritance of this disorder is autosomal recessive. The biochemical abnormality consists of a defect in galactose-1-phosphate uridyl transferase as a result of a mutation in GALT. This enzyme catalyzes the conversion of galactose-1-phosphate to uridine diphosphate galactose, and three forms of the enzyme are included in newborn screening. Several forms of galactosemia have been described, based on the degree of completeness of the metabolic block and some of these are due to mutations in other galactose pathway genes. In the typical (severe) form, the onset of symptoms is in the first days of life, after the ingestion of milk; vomiting and diarrhea are followed by a failure to thrive. Drowsiness, inattention, hypotonia, and diminution in the vigor of neonatal automatisms then become evident. The fontanels may bulge, the liver and spleen enlarge, the skin becomes yellow (in excess of the common neonatal jaundice), and anemia develops. In a small number, there is thrombocytopenia with


Neurology_Adams

Neurology_Adams. The fontanels may bulge, the liver and spleen enlarge, the skin becomes yellow (in excess of the common neonatal jaundice), and anemia develops. In a small number, there is thrombocytopenia with cerebral bleeding. Cataracts form as a result of the accumulation of galactitol in the lens. Studies of the outcome of surviving infants have shown delayed psychomotor development (IQ about 85), visual impairment, osteoporosis, ovarian failure, and residual cirrhosis, sometimes with splenomegaly and ascites. This seems to happen even with treatment. However, it is not known whether, in such patients, the treatment is always maintained through a critical developmental period. In one such patient, who died at age 8 years, the main change in the brain was slight microcephaly with fibrous gliosis of the white matter and some loss of Purkinje and granule cells in the cerebellum, and also gliosis (Crome). The diagnostic laboratory findings are an elevated blood galactose level, low glucose,


Neurology_Adams

Neurology_Adams. of the white matter and some loss of Purkinje and granule cells in the cerebellum, and also gliosis (Crome). The diagnostic laboratory findings are an elevated blood galactose level, low glucose, galactosuria, and deficiency of the applicable enzyme in red and white blood cells and in liver cells. The treatment is essentially dietary, using milk substitutes; if this is instituted early, the brain should be protected from injury.


Neurology_Adams

Neurology_Adams. A late-onset neurologic syndrome has also been observed by Friedman and colleagues in galactosemic patients who had survived the infantile disease. By late adolescence, they were cognitively delayed; some showed cerebellar ataxia, dystonia, and apraxia. One of these patients was middle-aged. Organic Acidurias of Infancy


Neurology_Adams

Neurology_Adams. Organic Acidurias of Infancy These have been divided into ketotic and nonketotic types. Most of these disorders are included in newborn screening. Among the ketotic types, the main one is propionic acidemia. This is an autosomal recessive disease caused by a primary defect in organic acid metabolism that is expressed clinically by episodes of vomiting, lethargy, coma, convulsions, hypertonia, and respiratory difficulty. The onset is in the neonatal or early infantile period; in time, psychomotor retardation becomes evident. Death usually occurs within a few months despite dietary treatment. Propionic acid, glycine, various forms of fatty acids, and butanone are elevated in the serum. As with other ketotic organic acidurias, high protein intake induces ketotic attacks. Marked restriction of dietary protein (specifically leucine) may prevent attacks of ketoacidosis and permit relatively good psychomotor development.


Neurology_Adams

Neurology_Adams. A number of other ketotic acidurias also occur in infancy. The most important of these are methylmalonic acidemia, isovaleric acidemia, beta-keto acidemia, and lactic acidemia. Each of these disorders can become manifest with profound metabolic acidosis and intermittent lethargy, vomiting, tachypnea, tremors, twitching, convulsions, and coma, with early death in about half the patients and developmental retardation in those who survive. Rare subtypes of methylmalonic acidemia respond to vitamin B12. Isovaleric acidemia is characterized by a striking odor of stale perspiration, which has given it the sobriquet “sweaty foot syndrome.” Numerous metabolic defects, most commonly of pyruvate decarboxylase and pyruvate dehydrogenase, are responsible for the accumulation of lactic and pyruvic acids. The enzymatic defect of isovaleric acidemia also has been demonstrated in a recurrent form of episodic cerebellar ataxia and athetosis and in a persistent form in mitochondrial encephalopathies


Neurology_Adams

Neurology_Adams. The enzymatic defect of isovaleric acidemia also has been demonstrated in a recurrent form of episodic cerebellar ataxia and athetosis and in a persistent form in mitochondrial encephalopathies (Leigh disease), as described further on in this chapter.


Neurology_Adams

Neurology_Adams. A separate and rare deficiency of aromatic l-amino acid decarboxylase has been described; the chemical signature is low levels of almost all catecholamines. This defect is associated with a peculiar movement disorder of oculogyric crises, dystonia and athetosis, and autonomic failure (see Swoboda et al). A type II glutaric acidemia has also been observed in the neonatal period and causes episodes of acidosis with vomiting and hyperglycemia. Multiple congenital anomalies of brain and somatic structures and cardiomyopathy are conjoined. A diet low in the specific toxic amino acid and supplements of carnitine and riboflavin are recommended, but the effects are unclear.


Neurology_Adams

Neurology_Adams. In the nonketotic form of hyperglycinemia, there are high levels of glycine but no acidosis. The notable diagnostic finding is an elevation of the CSF glycine, several times higher than that of the blood. The effects on the nervous system are more devastating than in the ketotic form. In reported cases (the authors and our colleagues have seen several), the neonate is hypotonic, listless, and dyspneic, with dysconjugate eye movements, opisthotonic posturing, myoclonus, and seizures. A few such neonates survive to infancy but are extremely cognitively impaired and helpless. Spongy degeneration of the brain has been reported both in this disease and in the ketotic form (Shuman et al). No treatment has been effective in severe cases. In an atypical milder form, with neurologic abnormalities that appear in later infancy or childhood, reduction of dietary protein and administration of sodium benzoate in doses up to 250 mg/kg/d have been beneficial. The use of dextromethorphan, which blocks


Neurology_Adams

Neurology_Adams. appear in later infancy or childhood, reduction of dietary protein and administration of sodium benzoate in doses up to 250 mg/kg/d have been beneficial. The use of dextromethorphan, which blocks glycine receptors, is said to be effective in preventing seizures and coma.


Neurology_Adams

Neurology_Adams. These are a group of six diseases caused by inborn deficiencies of the enzymes of the Krebs-Henseleit urea cycle; they are designated as N-acetyl glutamate synthetase, carbamoyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinic acid synthetase (citrullinemia), argininosuccinase deficiency, and arginase deficiency. Hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) and intrinsic protein intolerance are closely related disorders. They are identified by the finding of a persistent or episodic elevation of ammonia levels in the blood. A detailed account of these inherited hyperammonemic syndromes is contained in the review by Brusilow and Horwich.


Neurology_Adams

Neurology_Adams. The pattern of inheritance of each of these disorders is autosomal recessive except for OTC deficiency, which is X-linked dominant. Their clinical manifestations are a common expression of an accumulation of ammonia or of urea cycle intermediates in the brain; they differ only in severity, in accordance with the degree of completeness of the enzymatic deficiency and with the age of the affected individual. The one exception is arginase deficiency, which commonly appears during later childhood as a progressive spastic paraplegia with mental retardation. Clinically, it has been convenient to divide the hyperammonemias into two groups—one that presents in the neonatal period and another that becomes evident in the weeks or months thereafter. This division is somewhat artificial, the clinical presentation being more in the nature of a continuous spectrum governed by the biologic factors mentioned above and even extending to rare cases that have their first symptoms during adulthood.


Neurology_Adams

Neurology_Adams. In the most severe forms of the hyperammonemic disorders, the infants are asymptomatic at birth and during the first day or two of life, after which they refuse their feedings, vomit, and rapidly become inactive and lethargic, soon lapsing into an irreversible coma. Profuse sweating, focal or generalized seizures, rigidity with opisthotonos, hypothermia, and hyperventilation have been observed in the course of the illness. These symptoms constitute a medical emergency, but even with measures to reduce serum ammonia, the disease is usually fatal.


Neurology_Adams

Neurology_Adams. In less severely affected infants, hyperammonemia develops some months later, when protein feeding is increased. There is a failure to thrive, and attempts to enforce feeding or during periods of constipation (both of which increase ammonia production in the bowel) may result in bouts of vomiting, lethargy, hyperirritability, and screaming. Respiratory alkalosis is a consistent feature. Other manifestations are periods of alternating hypertonia and hypotonia, seizures, ataxia, blurred vision, and of confusion, stupor, and coma. During episodes of stupor, often precipitated by dehydration, an alimentary protein load, or minor surgery, brain edema may be seen by CT and MRI; with repeated relapses, the brain edema gives way to atrophy, which appears as symmetrical areas of decreased attenuation in the cerebral white matter. Between attacks, some patients with partial deficiency may be normal or show only a slight hyperbilirubinemia (DiMagno et al; Rowe et al). With decompensation, the


Neurology_Adams

Neurology_Adams. in the cerebral white matter. Between attacks, some patients with partial deficiency may be normal or show only a slight hyperbilirubinemia (DiMagno et al; Rowe et al). With decompensation, the bilirubin rises, as does ammonia, but neither reaches exceedingly high levels. After repeated attacks, signs of developmental delay with motor and mental retardation become evident, and the patient is vulnerable to recurrent infections. Two adult male patients in our care, who were married (but with azoospermia, which is common) and working at technically demanding jobs, came to medical attention because of bouts of visual blurring followed by stupor that evolved over hours (Shih et al, 1999). They had displayed an aversion to protein and milk products as children; in later life, after meals high in protein, they became encephalopathic, one with severe brain swelling. There are few phenotypic differences among the late-onset hyperammonemias except for argininosuccinic aciduria, in which


Neurology_Adams

Neurology_Adams. high in protein, they became encephalopathic, one with severe brain swelling. There are few phenotypic differences among the late-onset hyperammonemias except for argininosuccinic aciduria, in which excessive dryness and brittleness of the hair (trichorrhexis nodosa) are notable features, and the aforementioned arginase deficiency with spastic diplegia.


Neurology_Adams

Neurology_Adams. Diagnosis is established by the finding of hyperammonemia, often as high as 1,500 mg/dL. The precise diagnosis requires genetic testing. The primary hyperammonemias must be distinguished from the organic acidurias, including methylmalonic aciduria (see above), in which hyperammonemia can occur as a secondary metabolic abnormality.


Neurology_Adams

Neurology_Adams. In all the neonatal hyperammonemic diseases, the liver is often enlarged and liver cells appear to be inadequate in their metabolic functions, but how the enzymatic deficiencies or other disorders of amino acid metabolism affect the brain remains uncertain. It must be assumed that in some the saturation of the brain by ammonia impairs the oxidative metabolism of cerebral neurons, and when blood levels of ammonium increase (from protein ingestion, constipation, etc.), episodic coma or a more chronic impairment of cerebral functions occurs—as it does in adults with cirrhosis of the liver and portal-systemic encephalopathy. In the acutely fatal cases, the brain is swollen and edematous, and the astrocytes are diffusely increased in number and enlarged. The neurons are normal. Astrocytic swelling has been attributed to the accumulation of glutamate secondary to a suppression of glutamate synthetase. These changes have been reproduced in animals by the injection of ammonium chloride. When


Neurology_Adams

Neurology_Adams. has been attributed to the accumulation of glutamate secondary to a suppression of glutamate synthetase. These changes have been reproduced in animals by the injection of ammonium chloride. When the hyperammonemia is abrupt in onset and severe, the resulting combination of encephalopathy, brain swelling, and respiratory alkalosis simulates the Reye syndrome (see “Reye-Johnson Syndrome” in Chap. 39).


Neurology_Adams

Neurology_Adams. As in all forms of liver disease, valproic acid and other hepatic toxins may cause hepatic coma by further impairing the urea cycle enzymes. Notable are a few cases of inherited hyperammonemia that come to light in childhood or adulthood only after the administration of one of these drugs. Most cases of OTC present in the neonatal period with hyperammonemia but milder forms may appear later in life with episodic symptoms such as stupor, ataxia, and seizures. The other features have been mentioned above.


Neurology_Adams

Neurology_Adams. Treatment of the hyperammonemic syndromes The treatment of acute hyperammonemic syndromes is directed at lowering ammonia levels, initially by hemodialysis, exchange transfusions, and administration of phenylacetate and sodium benzoate, which may divert nitrogen from the ureagenesis cycle or act as ammonia scavengers. A report of treatment for 299 patients treated with phenylacetate (or phenylbutyrate) and benzoate showed an overall survival of 84 percent including a large proportion of children who were comatose on admission (see Enns et al).


Neurology_Adams

Neurology_Adams. With subsidence of the acute symptoms, a systematic form of management should be undertaken, as outlined by Brusilow and colleagues and by Msall and colleagues Arginine (50 to 150 mg/kg) should be added to the diet, as a deficiency of this substance may be responsible for the mental retardation and skin rashes associated with the native disorder. In more chronic cases, treatment consists of decreasing the ammonium load by the use of dietary protein restriction and by administration of oral antibiotics and lactulose. In infants with inborn errors of ureagenesis, there is a constant danger of recurrent episodes of hyperammonemia and coma, particularly in response to infections. In a few instances, careful management of the metabolic error has resulted in normal psychomotor development. Liver transplantation is curative.


Neurology_Adams

Neurology_Adams. These conditions are caused by a deficiency of a-keto acid dehydrogenase, resulting in the accumulation of the branched-chain amino acids leucine, isoleucine, and valine and the corresponding branched-chain a-keto acids, which may be detected in plasma and urine. Detection is part of most newborn screening panels. Maple syrup urine disease may be taken as the prototype. The pattern of inheritance of maple syrup urine disease is autosomal recessive and at least three types have been detected, each with a different genetic locus. The incidence is highest in Amish, Mennonite, and Jewish populations.


Neurology_Adams

Neurology_Adams. With the most-severe neonatal type, the infant appears normal at birth, but toward the end of the first week, poor feeding, intermittent hypertonicity, opisthotonos, and respiratory irregularities appear. These are followed by diminished neonatal automatisms, convulsions, severe ketoacidosis, and often coma and death toward the end of the second to fourth week. This disease is one of the causes of the malignant epileptic syndrome of early infancy (Brett). Four milder forms of the disease have been described. In these more chronic cases, feeding difficulties begin somewhat later in the early infantile period. They are manifest as recurrent infections, episodic acidosis, coma, and retarded growth and psychomotor development. Some of these patients, toward the end of the first year, may become quadriparetic or ataxic; or there may be only a nonspecific mental retardation. The disease derives its name from the maple syrup odor of the child’s urine, imparted by the chemical sotolon, that


Neurology_Adams

Neurology_Adams. quadriparetic or ataxic; or there may be only a nonspecific mental retardation. The disease derives its name from the maple syrup odor of the child’s urine, imparted by the chemical sotolon, that tests positively for 2,4-dinitrophenylhydrazine.


Neurology_Adams

Neurology_Adams. Other important laboratory findings in addition to increased plasma and urine concentrations of leucine, isoleucine, valine, and keto acids are secondary accumulation of a derivative of a-hydroxybutyric acid. The neuropathologic findings are uncertain. In the first acute case described, only interstitial edema of the brain was observed; but in more chronic cases, pallor and loss of myelin and gliosis of parts of the cerebral white matter that myelinate after birth may be found. This can be visualized on CT and MRI.


Neurology_Adams

Neurology_Adams. Treatment by severe restriction of foods containing branched-chain amino acids (leucine, isoleucine, and valine) allows reasonably normal mental development, but only if such restriction is begun in the neonatal period and maintained lifelong. A thiamine-responsive variant with a slightly different pattern of keto acids described by Prensky and Moser responds variably to 30 to 300 mg of thiamine. The acute episodes, which threaten life, may require peritoneal dialysis to remove the putative toxic metabolites; the episodes respond to the administration of glucose-amino acid mixtures that are free of branched-chain keto acids. Liver transplantation has the potential to be curative and obviate lifetime severe dietary restrictions.


Neurology_Adams

Neurology_Adams. In addition to maple syrup urine disease, there are a number of other metabolic disturbances, some of them of mitochondrial origin, that appear in the neonatal period or later and are marked by an organic acidemia. If they are severe, the infant develops a metabolic (lactic) acidosis soon after birth, with lethargy, feeding problems, rapid respirations, and vomiting. Or there may be irritability, jerky limb movements, and hypertonia. Later presentations take the form of feeding difficulties, repeated vomiting, hypotonia, and failure to thrive. With the passage of time, psychomotor retardation and drug-resistant seizures become evident. Metabolic stress—for example, intercurrent infection or surgical procedures—may precipitate an episode of lactic or ketoacidosis. The care of these patients during an acute illness is of extreme importance. See Lyon and colleagues for a more complete description. Rare cases, especially of biotidinase deficiency, can appear in early adulthood.


Neurology_Adams

Neurology_Adams. Biochemical studies may disclose a biotinidase deficiency, methylmalonic aciduria, glutaric acidemia, methylglutaconic acidemia, or any number of other organic acid abnormalities. Each can be identified by a now established genetic cause. As remarked above, some of these enzymes act in conjunction with a specific vitamin cofactor, so that exact diagnosis is imperative. The biotinidase deficiency may respond to 10 mg of biotin per day; the methylmalonic acidemia to 1 to 2 mg of vitamin B12 per day; maple syrup urine disease to 10 to 20 mg of thiamine per day; and glutaric acidemia types I and II to 300 mg of riboflavin per day. The administration of carnitine may increase the elimination of toxic metabolites.


Neurology_Adams

Neurology_Adams. These are extremely rare autosomal recessive disorders of sulfur metabolism due to a mutation in SUOX, manifest clinically during the neonatal period by seizures, axial hypotonia, reduced level of responsivity, and spasms with opisthotonos. There may be added dislocation of lenses, blindness, coloboma, and enophthalmos in combination with severe mental retardation and dysmorphic facial features (widely spaced eyes, long face and philtrum, puffy cheeks). There are no differences in clinical manifestations between pure sulfite oxidase deficiency and that associated with molybdenum cofactor deficiency. With survival into infancy, episodic confusion and stupor give way to seizures, mental retardation, and ataxia. In one of our cases, described by Shih and colleagues (1977), a stroke-like syndrome of hemiplegia and aphasia appeared during a relapse at the age of 4.5 years, and in one case, subluxation of the lenses and choreoathetosis appeared at 8 months of age.


Neurology_Adams

Neurology_Adams. The biochemical abnormality is the accumulation of sulfite and possibly sulfatase as a result of the enzyme deficiency. Cerebral atrophy with loss and destruction of white matter and gray matter (cerebral cortex, basal ganglia, and cerebellar nuclei) was observed in one postmortem examination. Increasing the intake of molybdenum or lowering the dietary intake of sulfur amino acids is a therapeutic possibility not yet fully evaluated. Diagnosis of Neonatal Metabolic Diseases


Neurology_Adams

Neurology_Adams. Diagnosis of Neonatal Metabolic Diseases An important clue, of course, is provided by the history of a neonatal disease or unexplained death earlier in the same sibship or in a male maternal relative. A history that protein foods are rejected by the infant, or even a history among relatives of a dislike of protein or feeding difficulties in infancy, should raise the suspicion of an inherited hyperammonemic disorder or an organic acidemia. Measurements of blood ammonia and lactate and of the urine for ketones and reducing substances (that react with cupric sulfate) are the key laboratory tests. A wide-spectrum screening program may disclose a biochemical abnormality; this is the optimal state of affairs, especially when this type of screening provides the information before symptoms appear.


Neurology_Adams

Neurology_Adams. A number of nonhereditary metabolic diseases must be distinguished from the hereditary ones in this period of life. Hypocalcemia is one of the most frequent causes of neonatal seizures; tetany, spasms, and tremulous movements are usually present. Its cause is unknown, but the disorder is easily corrected, with excellent prognosis. Symptomatic hypoglycemic reactions are frequent in neonates. Premature infants are the most susceptible. Seizures, tremulousness, and drowsiness occur with blood sugar levels of less than 30 mg/dL in the mature infant, and less than 20 mg/dL in the premature. Maternal toxemia and diabetes mellitus also predispose to hypoglycemia. Other causes of hypoglycemia are adrenal insufficiency, galactosemia, an idiopathic pancreatic islet-cell hyperplasia, the treatable fatty-acid beta-oxidation disorders, and a congenital deficiency of CSF glucose transport— causing persistent hypoglycorrhachia and refractory seizures unless blood glucose levels are kept high. The


Neurology_Adams

Neurology_Adams. fatty-acid beta-oxidation disorders, and a congenital deficiency of CSF glucose transport— causing persistent hypoglycorrhachia and refractory seizures unless blood glucose levels are kept high. The damaging effects of untreated hypoglycemia were well documented by Koivisto and colleagues. Also now identified is a disorder of CSF serine transport causing failure to thrive, severe developmental disability with spasticity and intractable epilepsy. The diagnosis is made by measuring CSF amino acids; treatment is with high-dose oral serine. Cretinism and idiopathic hypercalcemia are other recognizable entities that appear during this age period.


Neurology_Adams

Neurology_Adams. Aicardi has described a neonatal myoclonic syndrome, and Ohtahara has described a malignant neonatal seizure disorder. In some of the cases, the neonatal syndrome merged later with the West type of infantile spasms and the Lennox-Gastaut syndrome (see Chap. 15). Some of the cases had developmental abnormalities of the cerebrum, and severe developmental delay was the outcome. In other cases of this type, a familial coincidence was a feature; a metabolic defect has been suspected in these cases but never proved.


Neurology_Adams

Neurology_Adams. The hereditary metabolic diseases must also be distinguished from a number of other catastrophic disorders that occur at or soon after birth, such as asphyxia, perinatal ventricular hemorrhage with the respiratory distress syndrome of hyaline membrane disease, other hypotensive–hypoxic states, erythroblastosis fetalis with kernicterus, neonatal bacterial meningitis, meningoencephalitis (herpes simplex, cytomegalic inclusion disease, listeriosis, rubella, syphilis, and toxoplasmosis), and hemorrhagic disease of the newborn. These are described in Chap. 37, on the developmental diseases.


Neurology_Adams

Neurology_Adams. The hallmark of the hereditary metabolic diseases that affect the nervous system in infancy is failure to achieve psychosensorimotor milestones, or regression of previously attained behaviors. However, those that have their onset in the first year of life pose extraordinary problems in neurologic diagnosis. If the onset is in the first postnatal months, before the infant has had time to develop the normal complex repertoire of behavior, the first signs of disease may take the form of subtle delays in maturation rather than of psychomotor regression. Departures from normalcy include a lack of interest in the surroundings, a lack of visual engagement, poor head control, inability to sit up at the usual time, poor hand–eye coordination, and persistence of infantile automatisms. Of course, embryologic maldevelopment of the brain may have similar effects (Chap. 37), and systemic diseases and other visceral malformations—such as cystic fibrosis, renal disease, biliary atresia and congenital


Neurology_Adams

Neurology_Adams. maldevelopment of the brain may have similar effects (Chap. 37), and systemic diseases and other visceral malformations—such as cystic fibrosis, renal disease, biliary atresia and congenital heart disease, chronic infection, malnutrition, and seizures (with drug therapy)—may impede psychomotor development. Diagnosis becomes somewhat easier in the second half of the first year, especially if development in the first half had proceeded normally. Then an observant parent, usually one with older children, can perceive a loss of certain early acquisitions, attesting to the progressive nature of a disease.


Neurology_Adams

Neurology_Adams. The most distinctive members of this category of neurologic disease are the leukodystrophies and the lysosomal storage diseases. The leukodystrophies are a group of inherited metabolic diseases of the nervous system characterized by progressive, symmetrical, and usually massive destruction of the white matter of the brain and sometimes of the spinal cord; each type of leukodystrophy is distinguished by a specific genetic defect in myelin metabolism. In the lysosomal storage diseases, there is a genetic deficiency of the enzymes (usually one or more of the acid hydrolases) necessary for the degradation of specific glycosidic or of peptide linkages in the intracytoplasmic lysosomes, causing nerve cells to become engorged with material that they would ordinarily degrade. These metabolites eventually damage the nerve cell or its myelin sheath.


Neurology_Adams

Neurology_Adams. Most of these diseases are classed as sphingolipidoses. Brady in 1966 made the observation that in each of these disorders an increased quantity of sphingolipid accumulated in the brain and other tissues. The sphingolipids are a class of intracellular lipids that all have ceramide as their basic structure, but each has a different attached oligosaccharide or phosphorylcholine. The rate of synthesis of the sphingolipids is normal and their accumulation results from a defect of a specific lysosomal enzyme that normally degrades each of the glycoproteins, glycolipids, and mucopolysaccharides by removing a monosaccharide or sulfate moiety. It is the type of enzyme deficiency and accumulated metabolite, as well as the tissue distribution of the nondegradable substrate, that impart a distinctive biochemical and clinical character to each of the diseases in this category.


Neurology_Adams

Neurology_Adams. The concept of lysosomal storage diseases, introduced by Hers in 1965, excited great interest at the time because it provided the potential for prenatal diagnosis and the detection of carriers. The diagnosis of this group of diseases has also been facilitated by the use of CT, MRI, and evoked response techniques, which confirm the existence of leukodystrophies and by the electron microscopic examination of skin, rectal, or conjunctival biopsies, circulating lymphocytes, and cultured amniotic fluid cells, which discloses the lysosomal storage material in nonneural cells.


Neurology_Adams

Neurology_Adams. There are now more than 40 lysosomal storage diseases in which the biochemical abnormalities have been determined. The main ones are listed in Table 36-3, which was adapted originally from the review of Kolodny and Cable. Each has an identified genetic cause. In addition to the sphingolipidoses, which are the lysosomal storage diseases most likely to be encountered in the first year of life, the table includes the storage diseases that may not appear clinically until a later age (in childhood and adolescence)—to be considered later in this chapter. The frequency of each of the various types, as detected in a comprehensive study of the Australian population, is given by Meikle and colleagues and generally accords with the ordering below. A broad perspective on the frequency of the lysosomal disorders can be appreciated from the report of the Australian national referral laboratory. There were 545 cases (75 detected prenatally) over a 16-year period, a calculated frequency of 1 case per


Neurology_Adams

Neurology_Adams. disorders can be appreciated from the report of the Australian national referral laboratory. There were 545 cases (75 detected prenatally) over a 16-year period, a calculated frequency of 1 case per 7,700 live births. This is close to the estimate in the United States, which is approximately 1 per 5,000 births.


Neurology_Adams

Neurology_Adams. The more frequent types of lysosomal storage diseases are as follows: 1. Tay-Sachs disease (GM2 gangliosidosis) and variants such as Sandhoff disease 2. Infantile Gaucher disease 3. Infantile Niemann-Pick disease 4. Infantile GM1 generalized gangliosidosis 5. Krabbe globoid-body leukodystrophy 6. Farber lipogranulomatosis 7. Pelizaeus-Merzbacher and other sudanophilic leukodystrophies 8. Spongy degeneration (Canavan-van Bogaert-Bertrand disease) 9. Alexander disease 10. Zellweger encephalopathy 11. Lowe oculorenal-cerebral disease In the following descriptions, we have summarized the clinical and pathologic features of each of the diseases listed above and have italicized the characteristic clinical signs and corroborative laboratory tests. Leigh disease, which may appear in this age group, is described with the mitochondrial diseases, further on in this chapter. Tay-Sachs Disease (GM2 Gangliosidosis, Hexosaminidase A Deficiency, HEXA Mutation)


Neurology_Adams

Neurology_Adams. This is an autosomal recessive disease, mostly of Jewish infants of eastern European (Ashkenazic) background. The first description came from Tay, a British ophthalmologist, in 1881, and Sachs, an American neurologist, in 1887; they called it amaurotic family idiocy. The disease becomes apparent in the first weeks and months of life, almost always by the fourth month. The first manifestations are a regression of motor activity and an abnormal startle to acoustic stimuli, accompanied by listlessness, irritability, and poor reactions to visual stimuli. These are followed by a progressive delay in psychomotor development or regression (by 4 to 6 months), with inability to roll over and sit. At first, axial hypotonia is prominent, but later spasticity and other corticospinal tract signs and visual failure become evident. Degeneration of the macular cells exposes the underlying red vascular choroid surrounded by a whitish gray ring of retinal cells distended with ganglioside. The resulting


Neurology_Adams

Neurology_Adams. failure become evident. Degeneration of the macular cells exposes the underlying red vascular choroid surrounded by a whitish gray ring of retinal cells distended with ganglioside. The resulting appearance is of the cherry-red spot with optic atrophy (Fig. 36-1). These are observed in the retinas in more than 90 percent of patients (but are also characteristic of other storage diseases—see Table 36-4). In the second year, there are tonic-clonic or minor motor seizures and an increasing size of the head and diastasis of sutures with relatively normal-size ventricles; in the third year, the clinical picture is one of dementia, decerebration, and blindness. Cachexia becomes increasingly severe and death occurs at 2 to 4 years. The electroencephalogram (EEG) becomes abnormal in the early stages (paroxysmal slow waves with multiple spikes). Occasionally, one can find basophilic granules in leukocytes and vacuoles in lymphocytes. There are no visceral, skeletal, or bone marrow abnormalities


Neurology_Adams

Neurology_Adams. (paroxysmal slow waves with multiple spikes). Occasionally, one can find basophilic granules in leukocytes and vacuoles in lymphocytes. There are no visceral, skeletal, or bone marrow abnormalities by light microscopy.


Neurology_Adams

Neurology_Adams. The basic enzymatic abnormality is a deficiency of beta hexosaminidase A, which normally cleaves the


Neurology_Adams

Neurology_Adams. N-acetylgalactosamine from gangliosides. As a result of this deficiency, GM2 ganglioside accumulates in the cerebral cortical neurons, Purkinje cells, retinal ganglion cells, and, to a lesser extent, larger neurons of the brainstem and spinal cord. The enzymatic defect can be found in the serum, white blood cells, and cultured fibroblasts from the skin or amniotic fluid, the latter giving parents the option of abortion to prevent a presently untreatable and fatal disease. Testing for hexosaminidase A also permits the detection of heterozygote carriers of the gene defect. Detection of this enzyme defect is complicated by the fact that more than 50 mutations of the HEXA gene have been isolated, coding for alpha subunit of the beta hexosaminidases and the enzyme itself is normal in one form of activator enzyme deficiency. Only three mutations account for 98 percent of the form that is common in individuals of Jewish ancestry.


Neurology_Adams

Neurology_Adams. The brain is large, sometimes twice the normal weight. In addition, there is a loss of neurons and a reactive gliosis; remaining nerve cells throughout the CNS are distended with glycolipid. Biopsies of the rectal mucosa disclose glycolipid distention of the ganglion cells of the Auerbach plexus. In the past, this was used as a diagnostic method but has been obviated by prenatal and neonatal screening. Under the electron microscope, the particles of stored material appear as membranous cytoplasmic bodies. Retinal ganglion cells are distended with the same material and, together with fat-filled histiocytes, cause the whitish gray rings around the fovea, where there are no nerve cells, as noted above. Tay-Sachs disease is untreatable but can be prevented by testing all individuals of Jewish origin for the recessive trait. Where screening has been instituted the disease has become virtually eliminated. In Sandhoff disease, which affects infants of non-


Neurology_Adams

Neurology_Adams. In Sandhoff disease, which affects infants of non- Jewish origins, there is a deficiency of both hexosaminidase A and B, moderate hepatosplenomegaly, and coarse granulations in bone marrow histiocytes. The clinical and pathologic picture is the same as in Tay-Sachs disease except for the additional signs of visceral lipid storage. Occasionally, these visceral organs are not enlarged.


Neurology_Adams

Neurology_Adams. In recent years, numerous variants of hexosaminidase A and B deficiency have been identified. They differ clinically from Tay-Sachs disease in having a later onset, less-extensive brain involvement (cortical neurons relatively spared and intense affection of basal ganglia, as well as cerebellar and spinal neurons). Accordingly, the clinical expression of the variants appearing in childhood, adolescence, and adult life takes the form of athetosis, dystonia, ataxia, and motor neuron paralysis; mental function can be normal. The process has also been found in a few congenital cases in which there was a rapidly progressive decline of a microcephalic infant. Infantile Gaucher Disease (Type II Neuronopathic Form, Glucocerebrosidase Deficiency, GBA Mutation)