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REVIEW
Year : 2020  |  Volume : 23  |  Issue : 3  |  Page : 325-331
 

Vitamin-responsive movement disorders in children


1 Department of Pediatrics, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Pediatrics, Lady Hardinge Medical College, New Delhi, India

Date of Submission20-Dec-2019
Date of Acceptance21-Feb-2020
Date of Web Publication05-Jun-2020

Correspondence Address:
Dr. Suvasini Sharma
Associate Professor, Department of Pediatrics, Lady Hardinge Medical College, New Delhi - 110 001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.AIAN_678_19

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   Abstract 


Movement disorders in childhood comprise a heterogeneous group of conditions that lead to impairment of voluntary movement, abnormal postures, or inserted involuntary movements. Movement disorders in children are frequently caused by metabolic disorders, both inherited and acquired. Many of these respond to vitamin supplementation. Examples include infantile tremor syndrome, biotinidase deficiency, biotin-thiamine-responsive basal ganglia disease, pyruvate dehydrogenase deficiency, aromatic amino acid decarboxylase deficiency, ataxia with vitamin E deficiency, abetalipoproteinemia, cerebral folate deficiency, and cobalamin metabolism defects. Recognition of these disorders by pediatricians and neurologists is imperative as they are easily treated by vitamin supplementation. In this review, we discuss vitamin-responsive movement disorders in children.


Keywords: Biotin-thiamine-responsive basal ganglia disease, biotinidase deficiency, inherited metabolic disorders


How to cite this article:
Sondhi V, Sharma S. Vitamin-responsive movement disorders in children. Ann Indian Acad Neurol 2020;23:325-31

How to cite this URL:
Sondhi V, Sharma S. Vitamin-responsive movement disorders in children. Ann Indian Acad Neurol [serial online] 2020 [cited 2020 Jul 4];23:325-31. Available from: http://www.annalsofian.org/text.asp?2020/23/3/325/286082





   Introduction Top


Movement disorders in childhood comprise a heterogeneous group of conditions that lead to impairment of voluntary movement, abnormal postures, or inserted involuntary movements.[1] These are not only disabling but also disruptive to the development of the affected children. Children are in a vulnerable stage of brain development; thus, the ramifications of an untreated or inadequately treated movement disorder can be devastating- resulting in functional impairment and poor quality of life.[2] Therefore, there exists a pressing need for early identification of the type of movement disorder, consider the treatable options, and administer effective therapeutic interventions.

The catalytic properties of many enzymes depend on the participation of nonprotein prosthetic groups such as vitamins or minerals, as obligatory cofactors. Movement disorders may result due to nutritional deficiencies of certain vitamins (for example infantile tremor syndrome (ITS) due to vitamin B12 deficiency) or as a result of mutations affecting the utilization/binding of the vitamin cofactor or affecting metabolic pathway of the vitamin. Examples of genetic disorders include biotin (biotinidase deficiency),[3] biotin plus thiamine (biotin-thiamine-responsive basal ganglia disease [BTBGD]),[4] Coenzyme Q10 (certain CoQ10 defects),[5] creatine (cerebral creatine deficiency),[6] cyclic pyranopterin monophosphate (molybdenum cofactor complex deficiency caused by mutations in MOCS1),[7] folinic acid (cerebral folate deficiency, CFTD),[8] and vitamin B12 (certain cobalamin-related defects).[9] Examples of vitamin responsive disorders include infantile tremor syndrome, biotinidase deficiency, biotin-thiamine-responsive basal ganglia disease, pyruvate dehydrogenase deficiency, aromatic amino acid decarboxylase deficiency, ataxia with vitamin E deficiency, abetalipoproteinemia, cerebral folate deficiency, and cobalamin metabolism defects [Table 1]. In this review article, we present a summary of different vitamin-responsive movement disorders in children.
Table 1: Summary of vitamin responsive movement disorders

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   Infantile Tremor Syndrome (ITS) Top


ITS is classically defined by the tetrad of pallor, developmental delay/regression, skin pigmentation, and tremors. This typically affects infants between 6 and 24 months of age with a male predominance.[10] Maternal B12 deficiency is commonly associated, secondary to a vegetarian diet.[11] Almost all cases of ITS occur in exclusively breastfed infants with inadequate weaning. These infants usually have a normal antenatal and perinatal period, with normal development until 4 to 6 months of age. Thereafter, developmental slowing followed by developmental regression sets in. The infant gradually becomes less active and withdrawn with loss of interest in surroundings. Tremors are the most characteristic feature and tend to be coarse and jerky (myoclonus-like). Onset is usually focal from one of the upper extremities with rapid progression to generalized involvement, including facial, labial, lingual, and laryngeal musculature. Laryngeal involvement renders a distinctive tremulous goat-like cry. Tremors at times have been triggered or made worse by vitamin B 12 treatment. There are reports of another involuntary movement such as chorea or myoclonus coexisting with tremors.

The general examination of these infants suggests pallor, hyperpigmentation of dorsa of hands and feet (so-called “knuckle pigmentation”), and sparse lusterless hair with variable depigmentation.

Laboratory investigations may reveal anemia, which may be dimorphic with a predominance of macrocytic morphology of the red blood cells.[12],[13] Low serum vitamin B12 with normal serum and RBC folate levels is the hallmark.[10] Other laboratory findings include elevated serum homocysteine and urine methylmalonic acid.[10] MRI brain shows cerebral atrophy with or without delayed myelination.

The management of ITS involves nutritional rehabilitation and vitamin B12 supplementation. Pharmacologically, the infants are managed with intramuscular injection vitamin B12, 1 mg daily for 7 days followed by oral supplementation with cobalamin 500–1000 mcg daily for 3–6 months.[10]

The initial change is observed within 48–72 h of treatment in the form of improved general activity with the infants becoming more active and playful. The lost developmental milestones also begin to return. Tremors usually start decreasing in intensity within a week and the recovery is complete by 3–4 weeks.[10]

Biotinidase deficiency

Biotinidase deficiency [Figure 1]a presents with neurological and cutaneous symptoms including seizures, hypotonia, skin rash, and alopecia, usually between the second and fifth months of life.[14] Many children have ataxia, developmental delay, conjunctivitis, hearing loss, and visual problems including optic atrophy. Most but not all patients develop movement disorders. The commonest movement disorder is ataxia, followed by dystonia and cog-wheel rigidity.[3],[14]
Figure 1: The figures show the metabolism and role of biotin, cobalamin, and pyridoxine in various pathways. [Figure 1]a depicts the biotin-biotinidase cycle. [Figure 1]b illustrates the pathway for the metabolism of tyrosine and tryptophan, and the role of aromatic amino acid decarboxylase and its cofactor vitamin B6. [Figure 1]c highlights the metabolism of cobalamin to its to active forms: methylcobalamin and adenosylcobalamin and their role in methylation of homocysteine to methionine and conversion of methyl-malonyl-CoA to succinyl-CoA

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The diagnosis of biotinidase deficiency involves the demonstration of low serum biotinidase activity. Children with biotinidase deficiency are treated with pharmacologic doses of biotin (5–20 mg daily).[14] Essentially all symptomatic individuals improve clinically with biotin therapy. Seizures and movement disorders usually resolve within hours to days and the cutaneous manifestations usually resolve within weeks. Depending on the severity and frequency of episodes of metabolic and neurological compromise, many children with developmental delay rapidly achieve new milestones or regain those they lost.[15]

Biotin-thiamine-responsive basal ganglia disease (BTBGD)

BTBGD, also known as thiamine metabolism dysfunction syndrome-2 (MIM: 607483) is an autosomal recessive disorder caused by a mutation in the SLC19A3 gene.[16] BTBGD usually presents in children aged 3–10 years. Most commonly, it presents with recurrent subacute encephalopathy manifesting as confusion, seizures, ataxia, dystonia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia which, if left untreated, can eventually lead to coma and even death. Episodes are often triggered by febrile illness or mild trauma or surgery. Features of upper motor neuron lesion (hyperreflexia, ankle clonus, spasticity) and movement disorders including dystonia and cogwheel rigidity are nearly always present.[16],[17]

Brain MRI shows symmetric and bilateral increased T2 signal intensity in the central part of caudate head and putamen, as well as the involvement of the globi pallidi, thalami, infra- and supra-tentorial brain cortex, brain stem, and cerebellum. During acute crises, severe vasogenic edema can be observed; chronic changes include atrophy, necrosis, and gliosis in the affected regions. Laboratory investigations including TMS/GCMS are typically normal. The diagnosis of BTBGD is confirmed by identification of biallelic SLC19A3 pathogenic variants.[16],[17]

Biotin (5–10 mg/kg/day) and thiamine (300–900 mg) are given orally as early in the disease course as possible and are continued lifelong. Symptoms typically resolve within days.

Abetalipoproteinemia

Abetalipoproteinemia (Bassen-Kornzweig syndrome) is a rare autosomal recessive disorder of lipoprotein metabolism associated with severe fat malabsorption/steatorrhea from early infancy. It is caused by a mutation in the microsomal triglyceride transfer protein (MTTP) that catalyzes the transfer of lipids to specialized domains of the nascent apolipoprotein B polypeptide within the rough endoplasmic reticulum.[18]

Children fail to thrive during the first year of life, have stools that are pale, foul-smelling, and bulky. The abdomen is distended, and deep tendon reflexes are absent due to peripheral neuropathy, which is secondary to vitamin E deficiency. Intellectual development tends to be slow. After 10 years of age, intestinal symptoms are less severe, ataxia may develop with loss of position and vibration sensation and the onset of intention tremors.[18] The ataxia resembles that in isolated vitamin E deficiency but is associated with evidence for malabsorption. These latter symptoms reflect the involvement of the posterior columns, cerebellum, and basal ganglia. In adolescence, in the absence of an adequate supplement of vitamin E, atypical retinitis pigmentosa develops.[18]

The diagnosis is suggested by the presence of acanthocytes in the peripheral blood smear and extremely low plasma levels of cholesterol (<50 mg/dL); triglycerides are also very low (<20 mg/dL). Chylomicrons and very-low-density lipoproteins are not detectable, and the low-density lipoprotein fraction is virtually absent from the circulation. Patients with abetalipoproteinemia have mutations of the MTTP gene.

Management involves nutritional support and large supplements of the fat-soluble vitamins A, D, E, and K. Vitamin E (100–200 mg/kg/day) appears to arrest neurologic and retinal degeneration. Limiting long-chain fat intake can alleviate intestinal symptoms; medium-chain triglycerides can be used to supplement fat intake.[18]

Ataxia with vitamin E deficiency

The occurrence of childhood-onset recessive ataxia with vitamin E deficiency (AVED) is related to mutations in the gene (TTPA) encoding the α-tocopherol transfer protein (α-TTP) on chromosome 8.[19] A hepatic protein, α-TTP, is involved in the processing of vitamin E for transport in the chylomicrons. Deficiency of vitamin E, which has antioxidant properties, may cause neuronal degeneration. Purkinje cells are more vulnerable owing to their high metabolic activity and high oxygen demand.[20]

The childhood-onset disease has considerable resemblance to Friedrichs Ataxia. They present typically with progressive ataxia, titubation, and features of polyneuropathy with loss of proprioception and deep tendon reflexes. In addition, severe progressive cases may develop strabismus, dementia, cardiac arrhythmias, and dystonia or myoclonus. Retinitis pigmentosa and visual loss can accompany this syndrome.[20],[21]

Vitamin E levels should be obtained in all persons with sporadic ataxia of childhood or young-adult onset. Patients typically have less than 1.8 mg/L of vitamin E. Treatment with large doses of vitamin E stabilizes the neurological features, especially when started early in the disease but some features may show worsening despite therapy. The dose is at least 100 IU/kg/day of the most active d-form of alpha-tocopherol.[20],[21] The treatment must be continued for life.

Homocystinuria clinically

Homocysteine is an intermediate compound of methionine degradation and is remethylated to methionine. This methionine-sparing reaction is catalyzed by the enzyme methionine synthase, which requires a metabolite of folic acid (5-methyltetrahydrofolate) as a methyl donor and a metabolite of vitamin B12 (methylcobalamin) as a cofactor. This conversion of homocysteine to methionine is called as the re-methylation pathway. Alternatively, homocysteine is irreversibly metabolized to cysteine by the trans-sulfuration pathway. This starts with condensation of homocysteine and serine to form cystathionine, catalyzed by cystathionine beta-synthase (CBS). Deficiency of CBS leads to classic homocystinuria that is inherited as an autosomal recessive trait. The gene for CBS is located on chromosome 21q22.3.[21]

Phenotypically, there is a wide spectrum of severity, from individuals who are asymptomatic to those with severe multi-system disease, with a wide range of ages at presentation. Four main systems can be involved:(a) Eye: ectopia lentis and/or severe myopia; (b) Skeleton: excessive height and length of the limbs ('marfanoid' habitus), osteoporosis and bone deformities, such as pectus excavatum or carinatum, genu valgum and scoliosis; (c) CNS: developmental delay/intellectual disability, seizures, psychiatric and behavioral problems and extrapyramidal signs (dystonia): and (d) Vascular system: thromboembolism.

Plasma total homocysteine (tHcy) should be the frontline test for diagnosis of CBS deficiency. In untreated patients with CBS deficiency, tHcy concentrations are usually above 100 μmol/L. The diagnosis is very likely if elevated tHcy is accompanied by (a) high or borderline high plasma methionine concentrations, (b) low plasma cystathionine concentrations and (c) an increased methionine -cystathionine ratio. The genetic testing for involved gene should be considered in appropriate setting. Over 160 disease causing genetic variants in the CBS gene are known.

The phenotype broadly relates to pyridoxine-responsiveness. Treatment with high doses of vitamin B6 (100-500 mg/24 hr) causes dramatic improvement in patients who are responsive to this therapy. The degree of response to vitamin B6 treatment may vary across families. Some patients may not respond because of folate depletion; a patient should not be considered unresponsive to vitamin B6 until folic acid (1-5 mg/day) has been added to the treatment regimen. For patients who are unresponsive to vitamin B6, restriction of methionine intake in conjunction with cysteine supplementation is also recommended. The need for dietary restriction and its extent remains controversial in patients with vitamin B6 responsive form. In some patients with this form, addition of betaine may obviate the need for any dietary restriction. Betaine (trimethylglycine, 6 g/24 hr for adults or 200-250 mg/kg/day for children) lowers homocysteine levels in body fluids by remethylating homocysteine to methionine [Figure 1]c, which may result in elevation of plasma methionine levels. This treatment has produced clinical improvement (preventing vascular events) in patients who are unresponsive to vitamin B 6 therapy. To assess pyridoxine responsiveness after infancy, it is recommended to administer 10 mg/kg/day pyridoxine (100-500 mg/day) for 6 weeks; the plasma tHcy concentration should be measured at least twice before treatment and twice on treatment. The protein intake should be normal, folate supplements should be given and vitamin B12 deficiency should be corrected prior to testing. Patients who achieve plasma tHcy levels below 50μmol/l on pyridoxine are clearly responsive and do not need any other treatment. If the tHcy falls >20% but remains above 50μmol/L, additional treatment should be considered (i.e. diet and/or betaine). If tHcy falls by < 20% on pyridoxine, the patient is likely to be unresponsive.[21]

Cobalamin deficiency

Cobalamin is needed for just two metabolic reactions in humans: methylation of homocysteine to methionine and conversion of methyl-malonyl-CoA to succinyl-CoA [Figure 1]c. When cobalamin is deficient, these precursors accumulate; thus, detection of elevated circulating and urinary levels of methylmalonic acid and of total homocysteine is useful. In children, causes of cobalamin deficiency fall into three categories: dietary deficiency, abnormal absorption and transport, and inborn errors of cellular uptake and intracellular processing of cobalamins. The deficiency of intake usually presents in infancy with infantile tremor syndrome as described above. Genetic disorders can lead to errors of intracellular processing of cobalamins. Conversion of cobalamin to its active cofactors, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), requires a series of biochemical modifications that have been classified as cobalamin complementation groups A–J and for all of which distinct autosomal recessive genetic diseases are known.[9],[22]

Patients with complementation groups cblF, cblJ, cblC, and some with cblD have combined deficiencies of AdoCbl and MeCbl synthesis and are characterized by methylmalonic aciduria and elevated total homocysteine which is often associated with low plasma methionine and S-adenosylmethionine. Affected individuals present with feeding difficulties, failure to thrive, hematological (e.g. anemia, which is not always associated with macrocytosis, thrombocytopenia, and microthrombi), neurological (e.g. developmental delay, microcephaly, cerebral atrophy and hydrocephalus, hypotonia, seizures, dementia, and myelopathy), and metabolic acidosis. The cblD defect is variable with onset ranging from infancy to adolescence and includes poor feeding, lethargy and respiratory distress, developmental delay, megaloblastic anemia, seizures, hypotonia, gait abnormalities, cerebral atrophy and hydrocephalus, and cranial hemorrhage. Treatment with parenteral OHCbl 1 mg/day, betaine, folate, and carnitine partially improve the biochemical and clinical abnormalities.[9],[22]

CblD, cblE, and cblG defects, as well as severe methylenetetrahydrofolate reductase (MTHFR) deficiency, have deficient methionine synthesis associated with elevated total homocysteine and low methionine and S-adenosylmethionine in plasma. The most common clinical findings are poor feeding and vomiting with failure to thrive, megaloblastic anemia, and neurological disease, including developmental delay, cerebral atrophy, hypotonia or hypertonia, ataxia, neonatal seizures, nystagmus, and visual disturbances. Most patients are symptomatic in the first year of life. Treatment involves OHCbl or Methyl-Cbl, 1 mg intramuscularly, first daily, then once or twice weekly, together with betaine, folate, and methionine. This usually corrects the metabolic and hematological abnormalities.[9],[22] However, neurological symptoms respond only partially and severe neurological deficits often persist.

Cerebral folate deficiency

CFTD is caused by pathogenic mutations in the FOLR1 gene, which encodes folate receptor alpha (FRα).

Children with CFTD usually become symptomatic in late infancy. The delayed onset might be attributable to increased expression of folate receptor beta during the fetal and postnatal period that can compensate for the FRα defect.[23] The most common clinical finding in CFTD is developmental regression, with onset typically before the age of 3 years. Short drop attacks resembling infantile spasm leading to frequent myoclonic epileptic seizures resistant to antiseizure medication is often the initial presentation. Ataxia, truncal hypotonia and lower limb spasticity, autistic behavior, and microcephaly are frequent neurologic signs.[24]

Very low CSF concentrations of 5-methyltetrahydrofolate (usually below 5 nM), despite normal serum and RBC folate, are the biochemical hallmark of CFTD. MRI of the brain can be normal, while in a number of patients delayed myelination and cerebellar and cerebral atrophy can become apparent from the age of 18 months. MR spectroscopy indicates low concentrations of inositol and choline in the cerebral white matter. The diagnosis is confirmed by genetic testing of abovementioned mutation.[24]

Treatment is with a dose of 5 to 10 mg/kg/day of folinic acid. This results in normalization of cerebral choline and inositol content and correction of 5-methyl-THF. Frequently, clinical symptoms can only be partially corrected and require additional weekly intravenous injections of 50 to 100 mg folinic acid. In selected patients, intrathecal administration of folinic acid may be beneficial. For both intravenous and intrathecal application, the active 6S stereoisomer levofolinic acid should be preferred to the racemate of folinic acid to avoid brain accumulation of the inactive 6R form.[24]

Coenzyme Q10 deficiency

Patients with CoQ deficiency have reduced levels of CoQ in tissues, which can be caused either due to mutations in the genes participating in CoQ biosynthesis (primary CoQ deficiencies) or by defects not directly linked CoQ biosynthesis (secondary CoQ deficiencies). Primary CoQ deficiencies are usually associated with highly variable multisystemic manifestations and genetically caused by autosomal recessive mutations. Clinically, five major phenotypes have been associated with CoQ deficiency: 1) encephalomyopathy, 2) cerebellar ataxia, 3) infantile multisystemic form, 4) nephropathy, and 5) isolated myopathy. CNS is often affected in these patients, and cerebellar ataxia is the commonest manifestation. Other features include encephalopathy, hypotonia, seizures, intellectual disability, migraine, psychiatric disorders, muscle weakness and exercise intolerance, congenital hypotonia, upper motor neuron signs, dystonia and chorea, ptosis and ophthalmoplegia, retinitis pigmentosa, optic atrophy, oculomotor apraxia, deafness, and lipomas. These symptoms may be present in patients with mutations in any of the reported CoQ genes. The most frequent heart manifestation is hypertrophic cardiomyopathy. In other systemic involvements, they may present with nephrotic syndrome, dysmorphic features, and metabolic pathologies (diabetes mellitus, obesity, and hypercholesterolaemia).[5],[25]

The diagnosis of primary CoQ deficiency is established with the identification of biallelic pathogenic variants in any of the genes coding for one of the proteins directly involved in CoQ biosynthesis. Genome or specific gene sequencing is performed when decreased levels of CoQ or reduced combined activities of complex I + III and II + III in mitochondria of skeletal muscle biopsies are detected in patients.[5]

The response to CoQ 10 supplementation in patients with cerebellar ataxia is variable. Nonetheless, the treatment involves oral CoQ in a dose of 30 mg/kg/day in three divided doses.[5],[26]

Pyruvate dehydrogenase complex deficiency

Pyruvate is converted to acetyl-CoA by the enzyme pyruvate dehydrogenase (PDH) complex. The PDH is a mitochondrial matrix multienzyme complex and it is composed of at least four proteins: E1α, E1β, E2, and E3. Defects are most common in the E1α component. Mutations in the PDHA1 gene, which encodes the E1 subunit, account for approximately 80% of cases.

Although neurodevelopmental delay and hypotonia are most common, the clinical spectrum is broad. Neurological manifestations include hypotonia, weakness, ataxia, spasticity, cerebellar degeneration, seizures, and mental retardation. Ataxia can be intermittent with its median age at onset being about 18 months. Other motor symptoms can include recurrent acute dystonia, complex extrapyramidal movements in adults, and episodic peripheral weakness mimicking Guillain–Barré syndrome.[27],[28],[29]

PDH deficiency should be suspected in children with lactic acidosis, hypotonia, progressive or episodic ataxia, the Leigh disease phenotype, and recurrent polyneuropathy. The pyruvic acid concentration is elevated, and the lactate-to-pyruvate ratio is low. The blood concentration of lactate may be elevated between attacks; lactate and pyruvate concentrations are always elevated during attacks. Some children have hyperalaninemia as well. Analysis of enzyme activity in cultured fibroblasts, leukocytes, or muscle establishes the diagnosis. Molecular genetic testing is available. Structural brain abnormalities frequently include ventriculomegaly, microcephaly, agenesis of the corpus callosum, and bilaterally symmetrical lesions in the basal ganglia, thalamus, and brainstem.[29]

The ketogenic diet is a rational treatment for PDH complex deficiency. Patients are usually treated with thiamine (100–600 mg/day) and a high-fat (>55%), low-carbohydrate diet. Unfortunately, current treatments do not prevent disease progression in most patients.[29],[30]


   Conclusion Top


No one wants to miss a treatable condition, especially if the condition is as disabling as the movement disorder. It is imperative on all of us to find these treatable conditions at the earliest. We have tried to list some of these entities above and these have also been summarized in [Table 1]. Individually, these are rare but together they make a handful of disorders. Treatment of these diseases by administration of simple and easily available but often overlooked class of drugs can make a difference.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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    Tables

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