Table 2. Late-onset forms of childhood neurodegenerative disorders.

Disorder	Pathogenesis	Age of Onset	Disease Duration	Clinical Features in addition to Cognitive Dysfunction	Specific Diagnostic Studies with Suggested Order of Testing	Interventions in addition to Supportive Care
Mitochondrial disorders
MELAS61,66,68,69,70,118,119	Mutation in mitochondrial DNA gene MT-TL1 and MT-ND5	2-10 years	10-35 years	Normal early development, short stature, generalized tonic-clonic seizures, headache, anorexia, vomiting, exercise intolerance, proximal limb weakness, stroke-like episodes, lactic acidosis, sensorineural hearing loss	MRI (T2 hyperintensity in posterior cerebrum, DWI signal changes in stroke-like regions); Blood tests (elevated lactate); CSF (elevated lactate, elevated protein but <100 mg/dL); EEG (generalized epileptiform discharges); CT (basal ganglia calcification); EMG and NCS; muscle biopsy (ragged red fibers that stain for cytochrome c oxidase or ragged blue fibers that stain for succinate dehydrogenase); respiratory chain studies (defect in complex I or IV); genetic testing	Coenzyme Q10, L-carnitine
MERRF61,64,65,69,71,118	Mutation in mitochondrial DNA gene MT-TK	Childhood	-	Normal early development, myoclonus, generalized epilepsy, ataxia, weakness, hearing loss, short stature, optic atrophy, Wolff-Parkinson-White syndrome	MRI (basal ganglia calcification, bilateral putaminal necrosis, atrophy of brain stem and cerebellum); Blood tests (elevated lactate and pyruvate); CSF (elevatedlactate and pyruvate, elevated protein but <100 mg/dL); EEG (generalized spike and wave discharges with background slowing or focal epileptiform discharges); EMG and NCS; EKG; muscle biopsy (ragged red fibers that do not stain for cytochrome c oxidase but stain for succinate dehydrogenase); respiratory chain studies; genetic testing	Coenzyme Q10, L-carnitine
Kearns-Sayre syndrome62,63,67,69,72,118	Deletion of mitochondrial DNA	Before 20 years	-	Pigmentary retinopathy, progressive external ophthalmoplegia, cardiac conduction block, ataxia, deafness, diabetes mellitus and other endocrinopathies	MRI (hyperintensity of basal ganglia, brainstem, cerebral/cerebellar white matter);Blood tests (elevated lactate and pyruvate); CSF (elevated lactate and pyruvate, elevated protein >100 mg/dL); EMG and NCS; fasting serum glucose to screen for diabetes; EKG; muscle biopsy (ragged red fibers that do not stain for cytochrome c oxidase but stain for succinate dehydrogenase); respiratory chain studies; genetic testing	Coenzyme Q10, L-carnitine
Lysosomal Storage disorders
Tay Sachs disease73,74,79,81,87	AR mutation of HEXA gene on Chr15 -> decreased hexosaminidase A activity	3-6 months; adult onset forms reported	3-4 years; adult onset is longer duration	Weakness, dystonia, ataxia, motor neuron disease, psychiatric symptoms	Enzyme assay of serum or leukocytes (decreased or absent hexosaminidase A activity with normal or increased hexosaminidase B activity); genetic testing
Gaucher's disease type 2 and 375,82	AR mutation of GBA gene on Chr1 -> decreased gluco-cerebrosidase activity	Before 2 years	Type 2 is 1-2 years, type 3 is 30-40 years	Hepatosplenomegaly, pancytopenia, lung disease Type 2: bulbar signs, pyramidal signs. Type 3: oculomotor apraxia, seizures, myoclonus, bone disease	Enzyme assay of peripheral blood leukocytes (decreased glucocerebrosidase activity); bone marrow exam (Gaucher cells that stain with periodic acid-Schiff); genetic testing	Enzyme replacement therapy, bone marrow transplant
Niemann-Pick disease type C76,83,86,88	AR mutation of NPC1 on Chr18 or NPC2 on Chr14 -> decrease in protein transport across cell membrane	Mid-to-late childhood	20-30 years	Psychiatric symptoms, ataxia, vertical supranuclear gaze palsy, dystonia, seizures, dysarthria, dysphagia	MRI (atrophy of white matter tracts and bilateral hippocampus, thalamus, superior cerebellum, insula); fibroblast culture with decreased cholesterol esterification and filipin staining; genetic testing
Fabry's disease77,80,84,121	XLR mutation of GLA gene on ChrX -> decreased alpha galactosidase activity	4-8 years	33-37 years	Acroparesthesia, angiokeratoma, hypohidrosis, corneal and lenticular opacities, proteinuria, renal disease, cardio- and cerebrovascular disease	Enzyme assay of plasma, leukocytes, or cultured cells (decreased alpha galactosidase activity); genetic testing	Enzyme replacement therapy, reversible
Kufs disease (adult-onset form)78,85	AD mutation of CTSD on Chr11, PPT on Chr1, CLN3 on Chr16, CLN5 on Chr13, CLN4 on Chr20; AR mutation of CTSD on Chr11, PPT on Chr1, CLN5 on Chr13	15-50 years	10 years	Ataxia, pyramidal and extrapyramidal motor features Type A: myoclonic epilepsy Type B: behavior change	EEG (atypical spike and slow wave in type A or generalized slowing in type B); peripheral lymphocytes or skin biopsy (EM with curvilinear profiles, fingerprint profiles, granular osmophilic deposits); enzyme assay of leukocytes or fibroblasts (decreased PPT1, TPP-1, or cathepsin D activity); genetic testing
Leukodystrophies
Adrenoleuko- dystrophy89,95,101,108,122	XLR mutation of ABCD1 gene on ChrX -> decreased transport of VLCFA into peroxisomes for beta oxidation	4-8 years (20-30 years inadreno-myelo-neuro-pathy)	Variable	Behavioral changes with motor dysfunction, impaired vision and hearing, adrenal insufficiency; Adrenomyeloneuropathy: paraparesis, sphincter disturbance, sexual dysfunction; Carrier females have milder disease and later onset	MRI (T2 hyperintensity in parieto-occipital region with enhancing lesion margins); increased concentration of VLCFA in plasma or skin fibroblasts; genetic testing	Decr VLCFA in diet, steroid replacement therapy, bone marrow transplant
Meta-chromatic leuko-dystrophy (adult-onset form)89,96,102,104,109,123	AR mutation of ARSA gene on Chr22 -> decreased arylsulfatase A activity	16+ years	20+ years	Behavioral features with personality change, peripheral neuropathy, seizures, incontinence, motor symptoms including weakness and incoordination progress to spasticity	MRI (T2 diffuse symmetric periventricular hyperintensities with anterior to posterior gradient and cerebral atrophy); enzyme assay of leukocytes (decreased ARSA activity); urine sulfatides; MRS (decreased N-acetylaspartate); genetic testing	Bone marrow transplant
Alexander disease (juvenile- and adult-onset form)94,100,107,110,117	AD mutation of GFAP gene on Chr17 which encodes glial fibrillary acidic protein	4-10 years in juvenile-onset, young adulthood in adult-onset	Few years to decades	Bulbar/pseudobulbar signs, ataxia, seizures, megalencephaly, breathing difficulty	MRI (T2 frontal predominant extensive white matter abnormalities with hypointensity in periventricular regions; hyperintensity of basal ganglia and thalamus; brain stem abnormalities, and contrast enhancement); EEG (nonspecific, slow waves over frontal area); CSF (increased αβ-crystallin and heat shock protein 27, increased glial fibrillary acidic protein); genetic testing
Leukoen-cephalopathy with vanishing white matter (adult-onset form)91,111,116	AR mutation of EIF2B on Chr12 which initiates DNA translation; triggered by infection or trauma	Adulthood	-	Delayed motor and intellectual development, behavioral features, transient optic neuritis or hemiparesis, headache	MRI (T1 diffuse hypointensity of white matter; T2 diffuse hyperintensity of white matter); genetic testing
Pelizaeus-Merzbacher disease92,98,105,106,112	XLR mutation of PLP1 on ChrX which is component of CNS myelin	Before 5 years	30-70 years	Nystagmus, hypotonia, spastic quadriparesis, ataxia, dystonia, athetosis; Carrier females have milder symptoms	MRI (T2 and FLAIR hyperintensity in cerebral hemispheres, cerebellum, and brainstem with thin corpus callosum); genetic testing
Adult polyglucosan body disease93,99,103,113	AR mutation of GBE1 on Chr3 -> decreased glycogen branching enzyme activity	40+ years	Variable	Neurogenic bladder, gait abnormality, mixed upper and lower motor neuron disease, distal sensory loss	MRI of brain and spinal cord (paraventricular, subcortical, deep white matter changes that extend to cervical-medullary junction; generalized atrophy); EMG and NCS (axonal lumbosacral polyradiculoneuropathy); assay of skin fibroblasts or muscle (decreased glycogen brancher enzyme activity); sural nerve biopsy (intra-axonal polyglucosan bodies); genetic testing
Cerebro-tendineous xantho- matosis90,97,114,115	AR mutation of CYP27A1 on Chr2 -> decreased sterol 27-hydroxylase activity	20 years	-	Diarrhea in infancy, cataracts, xanthomas (Achilles), psychiatric features, pyramidal and cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, seizures	Blood tests (high plasma cholestanol, normal/low plasma cholesterol, decreased chenodeoxycholic acid, increased bile alcohols and glyconjugates); MRI (T2 bilateral hyperintensity of dentate nuclei and cerebral/cerebellar white matter); CSF (increased cholestanol and apolipoprotein B); enzyme assay of fibroblasts, liver, leukocytes (decreased sterol 27-hydroxylase activity); genetic testing	Cheno-deoxycholic acid, HMG-CoA reductase inhibitor

Abbreviations: CSF = cerebrospinal fluid

CT = computed tomography

MRI = magnetic resonance imaging

DWI = diffusion weighted imaging

EMG = electromyography

NCS = nerve conduction study

EEG = electroencephalography

EKG = electrocardiography

EM = electron micrography

MRS = magnetic resonance spectroscopy

FLAIR = fluid attenuated inversion recovery

AR = autosomal recessive

XLR = X-linked recessive

AD = autosomal dominant

Chr = chromosome

CNS = central nervous system

MELAS = mitochondrial encephalomyopathy lactic acidosis, and stroke-like episodes

MERRF = myoclonic epilepsy with ragged red fibers

VLCFA = very long chain fatty acids