Table 3

Features of some causes of progressive neurological and/or cognitive disease in adolescence

Estimated prevalence and conditionOMIM numberParaparesis/ pyramidal signsAtaxiaMyoclonus, seizuresExtra-pyramidalPeripheral poly-neuropathyVisual loss/symptomsFundoscopic abnormalitiesEye movement abnormalitiesStroke-like episodesEpisodic encephalopathyPersonality/ behavioural/dementiaOther commentsSpecific diagnostic tests
Conditions are grouped into indicative bands of relative prevalence, reflecting our experience in the north east of the UK (serving a population of approximately three million) although of course these may reflect local gene pool and other random effects. “HIGH” is intended to convey several active cases in a regional paediatric neurology centre; “MODERATE”, one or two at any one time, and “LOW” none currently. The one, two or three star rating for findings in each condition are again intended as very approximate reflections of frequency/importance.
HIGH
Friedreich ataxia22930******Scoliosis, late cardiac involvement, absent peripheral tendon reflexes, upgoing plantarsFrataxin mutations
Leigh syndrome late variantsVarious (220111, 161700, 266150, 308930, 516060, 185620, 220110)***********Characteristic symmetrical brainstem, basal ganglia changes on MRICSF lactate, respiratory chain assays
Primary torsion dystonia236200***Initial focal dystonia (typically foot) later progressing ± tremorDYT1 mutation
MODERATE
Homocystinuria236200********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 strokesHomocystinuria, plasma amino acids (raised homocysteine and nethionine)
Juvenile Huntington disease143100******Paternal FHx, failure of horizontal saccades. Caudate atrophy lateHuntingdin 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 yearsExtinguished ERG. Skin biopsy, CLN3 mutation
Kearns-Sayre and variants530000***********Cardiac conduction defects, high CSF protein, lactate. Ragged red fibres on muscle histologyCSF lactate, mtDNA studies
Niemann-Pick with vertical ophthalmoplegia257220******(First presentation in adolescence would be unusual.) Intention tremor, dysarthria. Supranuclear vertical gaze palsy. Modest organomegalySea blue histiocytes on bone marrow; cholesterol studies in cultured fibroblasts
LOW
Abetalipoproteinaemia200100*****“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-neuropathy300100*********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 SSPERaised VLCFA
Alexander disease203450****Very late onset variant (neonatal onset much more common). Dementia may be very slowly progressive. Progressive macrocephally, leukodystrophic MRIHistology on brain biopsy; GFAP gene mutation analysis
Cerebro-tendinous xanthomatosis (“cholestanolosis”)213700*********Insidious onset dementia, behaviour. Characteristic tendon xanthomas and cataracts. Palatal myoclonusLow plasma cholesterol; cholesterol metabolism abnormalities in urine, bile, CSF
Dopa responsive dystonia605407***Onset usually before adolescence. Clinical distinction sufficiently imprecise to warrant low threshold levodopa trialTherapeutic challenge with levodopa
DRPLA125370********Variable symptomatologyDRPLA mutation
Fabry disease301500*****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 strokesα Galactodisase activity
Hallervorden-Spatz234200*******Possible retinal pigmentationPathognomonic 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 pigmentationDNA mutation analysis for some
Hereditary spastic paraplegias (complicated)Many**???Various forms: AD, XLR. AR
Lafora disease254780*******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 gangliosidosis230650***Dysarthria and dystonia may be prominent. Very non-specific presentations possibleβ Galactosidase
Late variant GM2 gangliosidosis230700**************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)
MELAS540000*********High CSF protein, lactate. Ragged red fibres on muscle histologyMitochondrial DNA analysis
MERRF545000*******Short; deaf; mixed cerebellar and sensory ataxiaMitochondrial 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 MRIArylsulfatase A activity (rare variants with normal activity); sulfatiduria
Neuroacantho-
 cytosis200150*****Striatal changes on MRIAcanthocytes on film
Refsum disease266500********Retinal pigmentation, cataracts, cardiomyopathy, rash, deafness; high CSF protein. Episodic deteriorations. Dietary treatment ± plasmapheresis stabilises neurologyRaised plasma phytanic acid
SCA 7164500**********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 signsSCA 7 mutation analysis
Sialidosis type 1256550*******Macular cherry red spotUrinary sialyloligosaccharides; α neuraminidase in fibroblasts
SSPEn/a*****School failure and subtle cognitive difficulties can look very much like ALD, until the myoclonic epilepsy supervenesMeasles IgM in blood and IgG in CSF. Characteristic late EEG
Tangier disease205400***Pain and temperature insensitivity; tonsillar appearances; organomegallyHigh density lipoprotein very low
Unverricht-
 Lundborg disease254800****Synonymous with “Baltic myoclonus”. Myoclonus giving “jerky” quality to speech. Cognitive decline slow. Often notable benefit from valproateEPM1 mutation
Variant Creutzfeld-Jakob diseasen/a*********May present initially with psychiatric and cognitive symptoms. Reported in children as young as 12High T2 signal in pulvinar on MRI highly suggestive in appropriate clinical context
Wilson disease277900*****Consider in all unexplained neurological regressionCopper 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