HIGH
|
Friedreich ataxia | 22930 | ** | ** | | | ** | | | | | | | Scoliosis, late cardiac involvement, absent peripheral tendon reflexes, upgoing plantars | Frataxin mutations |
Leigh syndrome late variants | Various (220111, 161700, 266150, 308930, 516060, 185620, 220110) | | ** | ** | ** | * | | | ** | * | * | | Characteristic symmetrical brainstem, basal ganglia changes on MRI | CSF lactate, respiratory chain assays |
Primary torsion dystonia | 236200 | | | | *** | | | | | | | | Initial focal dystonia (typically foot) later progressing ± tremor | DYT1 mutation |
MODERATE
|
Homocystinuria | 236200 | | | | | | | *** | | *** | | ** | Learning difficulties may be static and longstanding with little to suggest regression. Lens dislocation highly suggestive. Marfanoid habitus. Should be considered in all young ischaemic strokes | Homocystinuria, plasma amino acids (raised homocysteine and nethionine) |
Juvenile Huntington disease | 143100 | | | | ** | | | | * | | | *** | Paternal FHx, failure of horizontal saccades. Caudate atrophy late | Huntingdin mutation analysis after appropriate pre-test genetic counselling |
Juvenile neuronal ceroid lipofuscinosis (Batten; CLN3) | 204200 | | | *** | * | | *** | ** | | | | *** | Retinal pigmentation. Visual loss (typically between 5–8 years of age) may predate onset of other signs by several years | Extinguished ERG. Skin biopsy, CLN3 mutation |
Kearns-Sayre and variants | 530000 | | ** | | | | | ** | *** | | ** | ** | Cardiac conduction defects, high CSF protein, lactate. Ragged red fibres on muscle histology | CSF lactate, mtDNA studies |
Niemann-Pick with vertical ophthalmoplegia | 257220 | | ** | * | | | | | *** | | | | (First presentation in adolescence would be unusual.) Intention tremor, dysarthria. Supranuclear vertical gaze palsy. Modest organomegaly | Sea blue histiocytes on bone marrow; cholesterol studies in cultured fibroblasts |
LOW
|
Abetalipoproteinaemia | 200100 | * | ** | | | * | | * | | | | | “Coeliac”-like like malabsorption syndrome in infancy. Head tremor a specific feature (cf Friedreich) | Acanthocytes on blood film. Characteristic cholesterol and plasma lipid profiles |
Adrenoleuko-dystrophy/ adrenomyelo-neuropathy | 300100 | ** | | | | ** | ** | | | | | *** | X linked recessive; female carriers may be symptomatic. Evidence of adrenal insufficiency (usually asymptomatic). The “myelopathy only” of AMN variant more common in adults than adolescents. See also comments on SSPE | Raised VLCFA |
Alexander disease | 203450 | ** | | | | | | | | | | ** | Very late onset variant (neonatal onset much more common). Dementia may be very slowly progressive. Progressive macrocephally, leukodystrophic MRI | Histology on brain biopsy; GFAP gene mutation analysis |
Cerebro-tendinous xanthomatosis (“cholestanolosis”) | 213700 | * | *** | | | | * | * | | | | *** | Insidious onset dementia, behaviour. Characteristic tendon xanthomas and cataracts. Palatal myoclonus | Low plasma cholesterol; cholesterol metabolism abnormalities in urine, bile, CSF |
Dopa responsive dystonia | 605407 | | | | *** | | | | | | | | Onset usually before adolescence. Clinical distinction sufficiently imprecise to warrant low threshold levodopa trial | Therapeutic challenge with levodopa |
DRPLA | 125370 | | *** | *** | | | | | | | | ** | Variable symptomatology | DRPLA mutation |
Fabry disease | 301500 | | | | | *** | | * | | * | | | X linked (males only, occasional affected female heterozygote). Corneal changes early (slit lamp only). Severe pain and oedema of extremities. Late focal signs from ischaemic strokes | α Galactodisase activity |
Hallervorden-Spatz | 234200 | * | | | *** | | | * | | | | ** | Possible retinal pigmentation | Pathognomonic MRI appearances of globus pallidus; recent mutations identified in pantothenate kinase genes may allow future genetic confirmation |
Hereditary spastic paraplegias (simple) | 182600, 182601 and others | ** | | | | | | * | | | | | Very slow; usually dominant Fhx; ± retinal pigmentation | DNA mutation analysis for some |
Hereditary spastic paraplegias (complicated) | Many | ** | | | | ? | ? | | | | | ? | Various forms: AD, XLR. AR | |
Lafora disease | 254780 | | | *** | | | * | | | | | *** | Visual hallucinations. Fairly rapid cognitive decline (cf Unverricht-Lundborg) | Axillary skin biopsy: PAS-positive inclusion in apocrine glands and/ or eccrine ducts. EPM2 mutation analysis |
Late variant GM1 gangliosidosis | 230650 | * | | | ** | | | | | | | | Dysarthria and dystonia may be prominent. Very non-specific presentations possible | β Galactosidase |
Late variant GM2 gangliosidosis | 230700 | *** | *** | * | * | ** | * | | | | | *** | Pure motor neuropathy with denervation and prominent amyotrophy, or a Friedreich-like syndrome. Visual loss can occur late: misdiagnosis as Batten possible? | Hexosaminidase A deficiency (some variants) |
MELAS | 540000 | | | ** | | | * | | * | *** | ** | | High CSF protein, lactate. Ragged red fibres on muscle histology | Mitochondrial DNA analysis |
MERRF | 545000 | | ** | *** | | | | | | | | ** | Short; deaf; mixed cerebellar and sensory ataxia | Mitochondrial DNA analysis |
Metachromatic leukodystrophy (late onset) | 250100, 249900 | ** | * | | | ** | | | | | | ** | (Presentation far more commonly in pre-school period with death in first decade.) CSF protein up; leukodystrophy on MRI | Arylsulfatase A activity (rare variants with normal activity); sulfatiduria |
Neuroacantho-
cytosis | 200150 | | | | *** | | | | | | | ** | Striatal changes on MRI | Acanthocytes on film |
Refsum disease | 266500 | | ** | | | *** | | *** | | | | | Retinal pigmentation, cataracts, cardiomyopathy, rash, deafness; high CSF protein. Episodic deteriorations. Dietary treatment ± plasmapheresis stabilises neurology | Raised plasma phytanic acid |
SCA 7 | 164500 | | *** | | * | | ** | ** | * | | | * | SCA7 in practice the only dominant spinocerebellar ataxia that presents in the paediatric age range. Pigmentary retinopathy/ maculopathy and visual failure are cardinal features. Late supranuclear ophthalmoplegias, dementia, and extrapyramidal signs | SCA 7 mutation analysis |
Sialidosis type 1 | 256550 | | | *** | | | ** | ** | | | | | Macular cherry red spot | Urinary sialyloligosaccharides; α neuraminidase in fibroblasts |
SSPE | n/a | | | ** | | | | | | | | *** | School failure and subtle cognitive difficulties can look very much like ALD, until the myoclonic epilepsy supervenes | Measles IgM in blood and IgG in CSF. Characteristic late EEG |
Tangier disease | 205400 | | | | | *** | | | | | | | Pain and temperature insensitivity; tonsillar appearances; organomegally | High density lipoprotein very low |
Unverricht-
Lundborg disease | 254800 | | | *** | | | | | | | | * | Synonymous with “Baltic myoclonus”. Myoclonus giving “jerky” quality to speech. Cognitive decline slow. Often notable benefit from valproate | EPM1 mutation |
Variant Creutzfeld-Jakob disease | n/a | | ** | ** | * | | | | * | | | *** | May present initially with psychiatric and cognitive symptoms. Reported in children as young as 12 | High T2 signal in pulvinar on MRI highly suggestive in appropriate clinical context |
Wilson disease | 277900 | | | | ** | | | | | | | *** | Consider in all unexplained neurological regression | Copper studies; slit lamp |
Wolfram syndrome (DIDMOAD) | 222300 | | | * | | | | ** | * | | | ** | Juvenile onset insulin dependent diabetes mellitus and optic atrophy cardinal. DI and variable cognitive/ psychiatric features reported. Autosomal recessive | |