Disorders of metabolism and neurodegenerative disorders associated with epilepsy

Introduction

Epileptic seizures play a variable part in inherited dis orders of metabolism and neurodegenerative disorders. The epilepsy may be nonspecific or take such a typical course that its clinical pattern or EEG features, or both, act as significant aids in early diagnosis.

Disorders with neonatal onset

Inborn errors of metabolism may present with neonatal seizures; may have alarming symptoms such as progressive drowsiness and 'irritability' before convulsions appear; or drowsiness and irritability may start coincidentally with a series of seizures. The presence of neurological symptoms as well as seizures suggests that the underlying disorder is destructive.

In any newborn with seizures, hypoglycemia, hypocal cemia, infection and hemorrhage should first be excluded. Antepartum fetal hypoxia/ischemia, meconium-stained amniotic fluid and low Apgar scores do not exclude inborn errors, particularly if further deterioration takes place. Non-optimal adaptation to the birth process may be the first indication of an inborn error. Amino acid disorders, including disorders of neurotransmitters

Vitamin B6 dependency

Vitamin B6 is present in various dietary products. The phosporylated active compound, pyridoxal-5'-phosphate, is required as a cofactor to glutamic acid decarboxylase, which catalyzes the formation of GABA ( γ-amino-butyric acid) from glutamate . In vitamin B6 depend ency, seizures are due to an inherited autosomal recessive disorder. Typically, they occur within hours after birth, are difficult to control by conventional antiepileptic ther apy, and respond promptly to administration of a high dose of pyridoxine intramuscularly or intravenously. They may be felt prenatally as hiccup-like fetal movements. However, sometimes seizures begin as late as 2 years of age, and additional clinical features occur.[1] The patho genesis of vitamin B6-dependent seizures is still unknown, but genetic analysis suggests linkage to chromosome 5q31. Diagnosis depends on demonstration that the seizures are controlled with pharmacologic doses of pyridoxine and recur when it is withdrawn. In any child who presents with refractory seizures with an onset before 2 years of age, or has seizures known to be familial, pyridoxine should be tried. The amount needed is not clear, but 100 mg (intravenously or intramuscularly) is recommended, and, if no improvement is observed within 10 min, additional l00 mg doses should be administered to a total of 500 mg, before excluding the diagnosis.[2] However, in general, the response will be quick. Facilities for resusci tation should be available: there is a possible danger of respiratory depression following the first large dose.

Folinic acid responsive seizures

Folinic acid (formyl-tetrahydrofolate)-dependent seizures are probably due to an inherited disease. In the cases reported,[3] treatment with folinic acid stopped the seizures within 1-5 days. All three confirmed inherited diseases of folate absorption and metabolism have been excluded. Folinic acid responsive seizures should be added to the list of possibilities when infants present with seizures within the first few weeks.

GABA transaminase (GABA-T) deficiency

GABA-T deficiency is another disorder in the metabolic routes of GABA which leads to neonatal seizures.[4] A single causative mutation has been identified in one of two siblings. Patients have accelerated somatic growth, megalencephaly, severe psychomotor retardation, and spongiform degeneration of myelin. Levels of GABA and β-alanine are increased in plasma, CSF and urine; and concentrations of homocarnosine and other GABA con jugates are increased in CSF. The fasting plasma growth hormone is elevated. GABA-T activity is decreased in liver biopsy specimens.

Nonketotic hyperglycinemia

This is an autosomal recessive disorder leading to excess glycine in CSF, blood and urine. Affected babies are usually asymptomatic at birth, but become obtunded, with apneic spells which progress to coma, and respiratory failure, between 7 h and 8 days.[5] Myoclonia, often stimu lus-evoked, as well as generalized seizures have been observed: these become difficult to manage with routine anticonvulsants.

The EEG in nonketotic hyperglycinemia, although highly characteristic with brief high-voltage paroxysms, predominantly over the vertex in a burst-suppression pattern, is not pathognomonic. However, in an initially normal neonate with a rapidly progressive encephalopathy, such a recording should always arouse the suspicion of nonketotic hyperglycinemia. Affected babies may die in the neonatal period or may spontan eously improve in vital functions and survive with severe brain damage. Their epilepsy may proceed to West syn drome.

In nonketotic hyperglycinemia, glycine is rela tively more elevated in CSF than in plasma. The highest CSF/plasma ratios are associated with the poorest out comes. Prenatal onset of the cerebral damage is indicated by the occasional finding of dysgenesis of the corpus cal losum.[6] No therapy has proved effective so tar, though a promising EEG response to dextromethorphan has been described.[7] High-dose benzoate reduces the glycine con centration to normal in plasma, and substantially in CSF, and dextromethorphan combined with benzoate has been effective in some patients.[8] Valproic acid must be avoided, since it tends to increase glycine levels. Otherwise, routine antiepileptic medication is appropriate.

Sulfite oxidase deficiency and molybdenum cofactor deficiency

Sulfite oxidase deficiency occurs in two forms: as an isolated enzyme defect and as part of a general deficiency of the molybdenum cofactor-containing enzymes. Both conditions lead to the accumulation of sulfite, and share the same clinical symptomatology. Severe and irreversible cerebral damage starts immediately after birth. Both defi ciencies have autosomal recessive inheritance. Patients with either defect may display abnormal facial features: enophthalmy, microcephaly and palatoschisis have been described.

Association with a Dandy-Walker complex has also been reported.[9] Convulsions usually start in the first week. Neuroimaging displays early signs of severe brain damage, which may appear very similar to the effects of perinatal asphyxia, with universal hypodensity and loss of distinction between cortex and central and subcortical white matter . Later, generalized shrinkage and cortical and thalamic calcification may continue to suggest that perinatal asphyxia is causative. Early central hypoventilation and ventilator dependency may precede death in the neonatal period.

Later symptoms include spastic quadriplegia and severe cognitive impairment, Neuropathologic descriptions suggest a severe destructive process is operating on both the cerebral cortex and the subcortical deep white matter.[10, 11] Loss of neurons, espe cially in the cerebral cortex, is extreme, and is more severe than is usually encountered in perinatal hypoxic-ischemic encephalopathy .

Sulfite oxidase deficiency should be suspected in any neonate where unexpected encephalopathy and seizures follow normal birth. Urine specimens screened for the presence of sulfite must be fresh: sulfite in the urine is oxidized to sulfate on stand ing. In both disorders, increased levels of sulfite, S-sulphocysteine, thiosulfate, taurine, and decreased cystine arc found in urine. In addition, in molybdenum cofactor deficiency, elevated levels of xanthine and hypoxanthine are found. No effective specific treatment is available.

Disorders of the urea cycle (hyperammonemias)

Inherited deficiency of an urea cycle enzyme may result in a severe neonatal encephalopathy, with coma and epileptic seizures. Carbamyl phosphate synthetase, argin-nosuccinic acid synthetase, argininosuccinate lyase, and ornithine transcarbamylase are most frequently affected. Ornithine transcarbamylase deficiency is X-linked, and although female carriers may be clinically affected, usu ally only males suffer the severe neonatal form. The other enzyme deficits are inherited by autosomal recessive modes. Patients with neonatal hyperammonemia behave normally initially. After birth, ammonia starts to accu mulate, leading to poor feeding and drowsiness, usually after the first 24 h. Focal or generalized seizures may occur, together with abnormal posturing and diaphoresis. Levels of ammonia above 400 µmol/L result in coma, and above 500 µmol/L in brain swelling and irreversible brain dam age .[12] Prompt diagnosis and treatment are needed, with strategies designed to reduce protein intake, enhance anabolism, utilize alternative pathways of nitrogen excretion and replace nutrients that are deficient. When an overwhelming illness presents in the newborn period, the prognosis is usually very poor, even with the most aggressive treatment.

Peroxisomal disorders

The biochemistry of these disorders is summarized in . Enzymes contained within the peroxisomal membrane act in tandem as metabolic pathways in the β-oxidation system which contains two sets ot enzymes with high affinity for very long straight-chain fatty acids, dicarboxylic acids, bile acid precursors, docosahexanoic acid precursor and very long branched-chain fatty acids, such as phytanic acid, and the latter's ex-oxidation product, pristanic acid.[13] The regular turnover of very long chain polyenoic fatty acids is mandatory for the maintenance of myelin and requires intact peroxisomes. Other peroxisomal metabolic pathways include part of the synthetic machinery for plasmalogens that constitute a quantitatively important part of complex lipids in the brain. Generalized peroxisomal diseases are peroxisomal assembly disorders: at least 12 genes are involved. Only those peroxisomal disorders that express abnormalities in the oxidation of very long chain fatty acids give rise to neonatal seizures. These include disorders of peroxisomal biogenesis assembly and isolated deficiencies of one peroxisomal ß-oxidation enzyme with intact peroxisomes.

Peroxisomal biogenesis disorders

Three clinical phenotypes are recognized. Zellweger syn drome presents with severe hypotonia, paresis, dystrophy and swallowing disorders: death occurs early. Infantile phytanic acid storage or infantile Refsum's disease is a moderate expression, and neonatal adrenoleukodystro phy lies in between these two.[14] All three are inherited as autosomal recessive disorders. Neonatal seizures occur in Zellweger syndrome and neonatal adrenoleukodystrophv. In Zellweger syndrome, characteristic external features and severe hypotonia are associated in all patients with neocortical dysplasia and clusters of neuronal hetero topia,[15] some of which show on MRI, but often they are of minute size and below the threshold of resolution.[16] The most characteristic, although not pathognomonic, sign in Zellweger syndrome is a steep parietal cleft which joins the Sylvian fissure to the superior part of the cerebral hemi sphere. Pachymicrogyria, patches of apparently thickened cortex, are also present, especially around the Sylvian fis sure and its abnormal extension . Outside the CNS, there are renal cortical cysts and periarticular calcification, especially visible around the knees, may be seen on radiologic skeletal survey. Pigmentary retinop athy, hepatic fibrosis or cirrhosis, and fatty changes in astrocytes also occur.[17] Initially status epilepticus is unusual in Zellweger syndrome, but seizures characterized by apneic spells, blinking, and generalized and partial clonic movements may be difficult to control. On EEG, continuous negative sharp waves and spikes are considered characteristic.[18]

In neonatal adrenoleukodystrophy, facial dysmorphism is less typical and neither renal cortical cysts nor par ticular calcifications are found. Malformations in the brain are limited to polymicrogyric patches of neocortex. Degenerative changes of progressive myelin breakdown with perivascular cuffing, are not unlike those in X-linked adrenoleukodystrophy. Late-onset cerebral white matter disease may occur in peroxisome biogenesis disorders.[19] Pigmentary retinopathy, sensory deafness and liver path ology are also found.

Single defects of peroxisomal β oxidation

Phenocopies of Zellweger syndrome and neonatal adrenoleukodystrophy exist as isolated peroxisomal β-oxidation defects with intact peroxisomes. The β-oxidation cycle requires an activating enzyme and three other enzymes for the repeating cycle to octanoic acid, which is further oxidized in the mitochondria.[13] Deficiency of peroxisomal acyl-CoA synthetase leads to X-linked adrenoleukodystrophy/adrenomyeloneuropathy in child hood or adulthood. Deficiency of acyl-CoA oxidase, or D- bifunctional protein or peroxisomal thiolase will cause neurological symptoms, including seizures in the neonatal period. In any neonate with seizures and severe generalized hypotonia that cannot be otherwise explained, a peroxiso mal disorder should be suspected. Determination of very long chain fatty acids in plasma or serum is the first step in diagnosis.

Definite elevation of C26 (hexacosanoic acid) is proof of a disorder of peroxisomal β-oxidation. Measurements of the concentrations of plasmalogens in erythrocytes and levels of bile acids in plasma are also important for more precise diagnosis. Fibroblasts should he sampled in any case of very long chain fatty acid eleva tion for final studies and as a reference for future prenatal diagnosis. There are no objections to giving standard antiepileptic medication to children with peroxisomal disorders, but dosages should be adjusted according to plasma levels when there is hepatic disease. Renal excre tion is usually unimpaired, even in the presence of renal cortical cysts.

Disorders arising in infants and children

Amino acid and organic acid disorders, including GABA-related disorders

Glutaric acidemia Type I

Glutaric acidemia type 1 is due to an autosomal recessive deficiency of the enzyme glutaryl-CoA dehydrogenase. Infants and children have megalencephaly, and on imaging a characteristic wide gap is seen between the frontal and parietal opercula, without initial signs of a destructive process. Starting acutely between 6 and 18 months, and often provoked by mild infection, episodes of decreased consciousness and hypotonia may be accompanied by seizures. Recovery is frequently incomplete, and severe incapacitating dystonia is usual.[20]

Disorders of the urea cycle with late onset

Inherited urea cycle disorders may present after the neo natal period with intermittent hyperammonemia leading to episodes of metabolic encephalopathy. Acute episodes are rarely accompanied by seizures. However, in arginase deficiency, a progressive spastic paraparesis may develop, together with epileptic seizures, even when hyperammone mia is well controlled.

Biotinidase deficiency

Biotin is a water-soluble vitamin which becomes part of four carboxylases. These are involved in fatty acid synthesis and incorporate and recycle their biotin compon ent with holocarboxylase synthetase and biotinidase. Deficiency of one of these latter enzymes leads to func tional deficiency of all the carboxylases. Holocarboxylase synthetase deficiency mainly manifests before 3 months of age, and biotinidase deficiency at later ages. A small proportion of synthetase-deficient patients have seizures, but a majority of the biotinidase-deficient patients have seizures both as initial manifestations and as major neurologic problems. Recognition may be delayed since the characteristic skin rash and alopecia only develop in a minority, and metabolic acidosis and ketosis are not seen initially. Seizures in unrecognized biotinidase deficiency are difficult to control by conventional anticonvulsants, but biotin therapy is effectives.[21] Outside periods of crisis, abnormal metabolic abnormalities in the urine may be minimal, though CSF/plasma ratios for lactate and 3-hydroxy-isovaleric acid may be elevated.[22] Biotinidase levels can be determined in plasma. Early recognition is important, because there is an excellent response to treatment. The pathology is similar to that of Leigh syndrome.[23]

Postneonatal vitamin B6 dependency

The initial impression that B6 dependency is limited to neonatal seizures had to be modified following several reports on postneonatal onset of therapy-refractory epilepsy with generalized, focal, myoclonic, partial motor, or partial complex types[24, 25] due to vitamin B6 dependency.

Succinic semialdehyde dehydrogenase deficiency

Succinic semialdehyde dehydrogenase deficiency, or 4-hydroxybutyric aciduria , is another inborn error of GABA-related metabolism which may be associ ated with epilepsy in almost 50 per cent of patients.[26] The clinical features vary from mild to severe, and include developmental delay, hypotonia, hyporeflexia, ataxia and behavioral problems. 4-Hydroxybutyric acid accumu lates in plasma, urine and CSF. Therapeutic intervention with vigabatrin is clinically beneficial in only about one third of patients.

Disorders of serine metabolism

The recognition of serine deficiency disorders depends on detection of low concentrations of amino acids in plasma and CSF. 3-Phosphoglycerate dehydrogenase (3-PGDH) deficiency is characterized by congenital microcephaly, severe delayed psychomotor development presenting in the first months of life and the onset of intractable epilepsy soon after. EEGs show either hypsarrhythmia or severe multifocal epileptic abnormalities with poor back ground activity.[27, 28] Brain MRI may demonstrate pro found reduction in the white matter volume and cerebral hypotrophy. Treatment with oral L-serine and glycine has beneficial effects on the epilepsy and brain white matter abnormalities.[29] EEG abnormalities can persist for some months after clinically manifest seizures have stopped. Plasma amino acids must be measured in the fasting state, because serine and glycine can be normal after feeding. In CSF, serine concentrations are always decreased in 3-PGDH deficiency.

Disorders of amine metabolism

Disorders of tetrahydrobiopterin metabolism ('malignant phenylketonuria')

At least five enzyme deficiencies lead to disordered tetrahydrobiopterin (BH4) homeostasis.[30] Typically the patient suffers from neurological deterioration despite excellent dietary control of the hyperphenylalaninemia. The deterioration may include seizures, although the main symptoms are extrapyramidal.

Aromatic amino acid decarboxylase deficiency

Serotonin and dopamine are depleted because the com mon decarboxylase which acts on L-DOPA and on 5-hydroxytryptophan (5-HTP) is deficient[31] . Since phenylalanine is not elevated, biogenic amines must be determined. If untreated, the symptoms are very similar to those in the defects of BH4 metabolism: hypotonia, oculogyric crises, extrapyramidal symptoms, defective temperature regulation and later hypotension.

Disorders of pyrimidine metabolism

Dihydropyrimidine dehydrogenase deficiency

Uracil and thymine accumulate. Affected patients may have mental retardation, microcephaly and epilepsy,[32] though some have only epilepsy.

Glucose transporter deficiency[33]

Repeated generalized seizures, with normal EEG, start within a few months after birth. The CSF/blood ratio for glucose is decreased and CSF lactate is low, suggesting that there is diminished availability of blood glucose to the brain. A glucose transporter deficiency in red blood cells has been proven. An identical transporter, which is encoded by the GLUT1 gene, exists in brain endothelial cells and astroglia. Patients improve dramatically with the provision of an alternative energy source to the brain, i.e. a ketogenic diet.

Creatine deficiency

Creatine biosynthesis involves arginine:glycine amidino transferase and guanidinoacetate methyltransferase (GAMT) as enzymes, and glycine arginine and S adenosylmethionine as substrates. The clinical presenta tion in GAMT deficiency[34] may be severe or moderate. Patients with severe phenotypes have intractable epilepsy, early developmental delay and extrapyramidal symp toms. Characteristic biochemical findings include brain creatine deficiency (seen on in vivo proton magnetic res onance scanning), and accumulation of guanidinoacetate in brain and in body fluids. Systemic depletion of creatine and creatine phosphate leads to low urinary creatine excretion, and low creatine concentrations in plasma and CSF. Clinical, biochemical and neuroradiologic improve ment follows creatine supplementation. X-linked creatine transporter defect has been described with early develop mental delay, seizures, a region of T2-weighted hyperin tense signal in the right posterior white matter, and brain creatine depletion detected by proton MRS.[35] In contrast to GAMT deficiency, brain creatine deficiency is not reversible by oral creatine substitution, guanidinoacetate concentrations in plasma and urine are normal, and creatine values are elevated in urine and plasma. Arginine:glycine amidinotransferase deficiency is associated with a response similar to that observed in patients with GAMT deficiency when treated with oral supple ments of creatine monohydrate.[36]

Disorders of the respiratory chain and pyruvate dehydrogenase complex

Seizures caused by mitochondrial disorders are mainly related to deficiencies of the respiratory chain and the pyruvate dehydrogenase complex (PDHC). Less frequently a deficiency of the citric acid (Krebs) cycle or pyruvate carboxylase may be involved. Disorders of mitochondrial β-oxidation affect the brain indirectly by causing hypoglycemic episodes. Point mutations in nuclear or mitochondrial DNA (mtDNA), large deletions in mtDNA, and variable tissue distribution of mutant mtDNA cause many different disorders. Depletion of mtDNA or inter genomic signaling defects are possible.[37] Leigh syndrome; Alpers disease; mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS); and myoclonus epilepsy and ragged-red fibers (MERRF) are caused by respiratory chain deficiency. Leigh syndrome may also be caused by deficiency of PDHC. Defined by its pathologic features, clinically Leigh syndrome is highly variable, with a remitting course and exacerbations often provoked by intercurrent infections. Hypotonia, vomit ing and brainstem symptoms predominate.

Leigh syndrome has become firmly linked to various sites of the respiratory chain and PDHC.[38] Lactic acidemia and ele vated lactic acid in the CSF are usual. Seizures were seen at onset in 8 per cent of 173 proven cases.[39] Therapy-resistant epilepsy and status epilepticus are less frequent. In Alpers' disease, there is severe degeneration of the cor tex basal ganglia and nuclear systems in the brainstem.[40] Especially in infants, cortical atrophy is extreme and devastating, so that cortical layers become indistinct. After normal early development, convulsions and myoclonia appear before 2 years, with coincident arrest in motor development. A special type is combined with diffuse liver disease.[41]

All affected children develop seizures, often with an explosive onset. Frequently, these consist of isolated twitching of one or other limb, sometimes con tinuing incessantly for weeks.[42] The EEG is characterized by focal very high voltage, very slow waves, alternating with low voltage superimposed polyspikes, usually con tralateral to the focal seizures. The electroretinogram is normal. An association between Alpers' disease, ragged red muscle fibres and elevation of lactic acid in blood, urine and CSF may be found.[43] In addition, complex I deficiency, complex IV deficiency and a defect in the citric acid cycle between succinyl-CoA and fumarate have been reported. In the hepatocerebral form of Alpers' disease, there is an apparent specific vulnerability to toxic effects of valproic acid.

MELAS syndrom[44] can start at any time from age 3 to 40 years. Progressive encephalopathy is typically accom panied by migraine-like headache, dementia, seizures and stroke-like episodes.[45] Lactic acidosis is usual, and ragged red fibers are seen in muscle biopsies. The inheritance is matrilinear.[37]

MERRF can start in childhood with bursts of myoclonus, seizures, intention tremor, ataxia, mental deterioration, muscular weakness and pes cavus. Lactic acidemia is usual. Neuropathologic findings show degeneration of cerebellar cortex, dentate and red nuclei, globus pallidus and subthalamic nucleus.[46] MERRF is transmitted by maternal inheritance. It should be distinguished from Ramsey-Hunt disease.

Peroxisomal disorders

The most important peroxisomal disease with onset after the neonatal period is X-linked adrenoleukodystrophy. Seizures are the presenting symptom in a small minority, and can be secondary to hypoglycemia, associated with the adrenal insufficiency.

Lysosomal disorders

Lysosomal disorders are typically storage disorders with a progressive course. The propensity to epileptic seizures varies, but is reported as 34 per cent in fucosidosis,[47] and prominent in α-N-acetylgalactosaminidase deficiency (Schindler's disease).[48] Both sialidosis and galactosiali dosis may present as the cherry-red spot-myoclonus syndrome. Early-onset sialidosis presents between 0 and 10 months, and the late-onset type between 8 and 25 years. Galactosialidosis presents between birth and 6 years: symptoms largely overlap with those of pure sialidosis. Sphingolipidoses that preferentially affect metabolism of myelin (lysosomal leukodystrophies), such as metachromatic leukodystrophy and Krabbe's disease, eventually cause epilepsy, but only some time after the onset of functional regression: they usually respond to antiepileptic medication.

Neuronal ceroid lipofuscinoses

The neuronal ceroid lipofuscinoses, a 'new' group of lysosomal disorders, are a large group of autosomal recessive neurodegenerative disorders with clinically and genetic ally different features. All of these disorders are character ized by accumulation of autofluorescent storage material, ceroid, in lysosomes of neurons and other tissues. Previously, diagnoses of neuronal ceroid lipofuscinoses were based on clinicopathologic findings and age of onset, and the main types were known by eponymous names: Santavuori-Hagberg (infantile type), Jansky-Bielschowsky (late infantile type) and Spielmeyer-Vogt (juvenile type). However, reports on variant types, new entities and knowledge about the genes necessitated another delineation (Table 4E.1). The adult neuronal ceroid lipofuscinoses, Kufs disease, is not included in this review. The known gene products appear to be lysosomal enzymes (NCL1 and NCL2) or lysosomal membrane proteins (NCL3 and NCL5). All types of NCL cause progressive visual and men tal decline, motor disturbance and epilepsy.[49] Except for Northern epilepsy, all childhood neuronal ceroid lipofusci noses belong to the group of myoclonic epilepsies and have retinal degeneration with extinguished electroretinogram.[50]

Infantile neuronal ceroid lipofuscinosis (Santavuori-Hagberg Type, CLN1)

After normal early development, decline starts between 8 and 24 months with ataxia, muscle hypotonia followed by spasticity, visual loss, loss of interest, prominent myoclonus, epileptic seizures and 'knitting' hyperkinesia. Microcephaly, usually present at onset, is progressive. A vegetative state is reached by 3 years. EEC shows progressive diminution of voltage until the third year, after which the recording becomes isoelectric. Electroretinographyis of lowered amplitude, even at an early stage.[51] Optic atro phy with brown discoloration of the macular region is seen later. Death is mostly between 5 and 10 years. Extreme cerebral atrophy is seen at autopsy, when microscopy shows disappearance of cortical neurons, with storage of auto fluorescent material in any which remain. The storage material is also seen widely in reticuloendothelial and other cell types outside the CNS. Diagnosis by biopsies (skin, conjunctiva, skeletal muscle, lymphocytes) should be possible, but is confirmed by finding deficiency of palmi toyl protein thioesterase activity. Mutations in the CLN1 gene can be associated with five different phenotypes.

Late infantile neuronal ceroid lipofuscinosis (JANSKY-BIELSCHOWSKY DISEASE, CNL2)

Onset is between 2 and 4 years of age, with rapidly pro gressing epilepsy, ataxia and blindness. Spastic paresis follows. Epilepsy takes the form of generalized tonic-donic seizures, drop attacks and massive myoclonus. Progression of myoclonus ultimately leads to a permanent myoclonic state. Patients usually die before 8 years. Optic atrophy and retinopathy develop early in the disease. The elec troretinogram, which is negative at an early age, is a highly suggestive test at the beginning of the disease. A grossly enlarged visual evoked potential and short generalized discharges in the EEG following each flash at low fre quency stroboscopy[52] are also helpful in diagnosis. Storage and atrophy occur in the brain, but are much less severe than in the infantile type. So-called curvilinear and other profiles within lysosomal membranes are found widely in cerebral neurons, and in eccrine sweat glands, striated-muscle cells, and Schwann cells. Lymphocytes may also dis play storage material, in some cases. The diagnosis can be confirmed by analysis of tripeptidyl peptidase I activity in lymphocytes, fibroblasts, and brain. The same CLN2 gene may cause juvenile, as well as late-infantile, disease.

Neuronal ceroid lipotuscinoses in childhood
Disease	Gene	Diagnostics
Infantile, classic (Santavuori-Hagberg)	CLN1	Palmitoyl protein thioesterase activity
and later ages of onset up to adulthood		Mutation analysis
Late infantile, classic (Jansky-Bielschowsky)	CLN2	Tripeptidyl peptidase I activity
and later ages of onset up to juvenile		Mutation analysis
Finnish variant late infantile	CLN5	Transmembrane CLN5 protein Mutation analysis
Variant late infantile	CLN6	Transmembrane CLN6 protein Mutation analysis
Variant late infantile, Turkish	CLN7	?
Northern epilepsy	CLN8	Transmembrane CLN8 protein Mutation analysis
Juvenile, classic (Spielmeyer-Vogt)	CLN3	Transmembrane CLN3 protein Mutation analysis

Juvenile neuronal ceroid lipofuscinosis (SPIELMEYER-VOGT, CLN3)

Onset is between 4 and 8 years with retinal blindness, later tollowcd by dementia, generalized seizures, regression of motor functions with a Parkinsonian syndrome and death alter 20 years. Although present, epilepsy is not a major problem. The lysosomal protein battenin is defective in juvenile NCL. However, no biochemical assay is currently available for the diagnosis.

Other types of neuronal ceroid lipofuscinosis in children

• Finnish variant late-infantile (CLN5). The clinical features mostly reflect the late-infantile type, but the onset is at a later age and the electronmicroscopic findings differ from those in CLN2.[53] Biochemical diagnosis is not yet available.
• Variant late-infantile/atypical NCL (CLN6) and the Turkish variant late-infantile NCL (CLN7) resemble the classic late-infantile NCL.
• Northern epilepsy or progressive epilepsy with mental retardation (CLN8) becomes apparent between 5 and 10 years,[54] All patients have generalized tonic-clonic or complex partial seizures. Mental retardation begins 2-5 years after the onset of seizures.

Seizures in some inherited neurodegenerative disorders

Rett syndrome

Typical Rett syndrome in girls is characterized by an initial 6-18 month period of apparently normal development followed by loss of learned language and motor skills. In the more advanced stages, epilepsy is usual, but occasion ally seizures, or even status epilepticus, are the initial events, and may obscure the otherwise clear symptoms. General ized tonic clonic seizures are most common, with partial simplex seizures next commonest.[55] Neuroimaging sug gests that the decreased brain volume results from global reductions in both gray and white matter.[56] The identifi cation of the causative gene, X-linked methyl-CpG binding protein 2 (MECP2), provides a diagnostic test.[57] Mutations in the MECP2 gene have been found in 70-90 per cent of classic Rett patients. Recently atypical variants and affected males have been identified, making the spectrum of associations with the MECP2 mutation wide, ranging from males with early-onset lethal encephalopathy to adults with severe mental retardation. Depending, at least in part, on the patterns of X-chromosome inactivations[58] female cases can range from asymptomatic or mildly mentally retarded cases to severe variants with congenital onset.

PEHO syndrome

Progressive encephalopathy with oedema, hypsarrhyth mia and optic atrophy (PEHO), also known as infantile cerebello-optic atrophy, is an autosomal recessive disorder which presents as an early-onset neurodegenerative dis order with therapy-refractory infantile spasms, profound psychomotor retardation, hypotonia, absent visual contact and optic atrophy. Microcephaly and subcutaneous edema of the limbs and face follow. There is severe and generalized cerebellar atrophy, and some macroscopic atrophy and myelination delay in the cerebral hemispheres. Neu ropathologies EEG, neuroradiologic, and ophthalmologic findings give a fairly consistent and recognizable pattern .[59, 60]

Key points

• In disorders of metabolism and neurodegenerative disorders, epilepsy is usually part of a generalized encephalopathy
• In the neonate, the following conditions should be considered: vitamin B6 dependency, folinic acid responsive seizures, GABA-T deficiency, nonketotic hyperglycinemia, sulfite oxidase deficiency, hyperammonemia and peroxisomal disorders
• Seizures in infants and children can be secondary to disturbances of amino- and organic acid metabolism, disorders of the urea cycle with late onset, biotinidase deficiency, postneonatal vitamin B6 dependency, disorders of amine metabolism, glucose transporter deficiency, disorders of the respiratory chain and pyruvate dehydrogenase complex, peroxisomal and lysosomal disorders, neuronal ceroid lipofuscinosis, Rett and PEHO syndromes
• In some conditions, e.g. biotinidase deficiency and vitamin B6 dependency, correction of the metabolic disturbances can control otherwise resistant seizures
• Valproic acid should not be given in the cerebrohepatic form of Alpers' disease, or in hyperglycinemia

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Key Sources[62]

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    Chapter 4e Disorders of metabolism and neurodegenerative disorders associated with epilepsy by Bwee Tien Poll-the

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