Treatable vitamin- and/or cofactor-responsive neurometabolic disorders which must not be missed

Administrator: Ingrid Tein, Canada

Dr. Ingrid Tein
Division of Neurology, Dept. of Pediatrics, Genetics and Genome Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, Canada
ingrid.tein@sickkids.ca
Update on the high affinity plasmalemmal carnitine transporter (OCTN2) deficiency
The high affinity plasmalemmal carnitine transporter (OCTN2) deficiency, also known as the carnitine uptake defect (CUD), is an autosomal recessive disorder which in its severest form is an infantile-onset, formerly lethal disorder presenting with recurrent episodes of hypoglycemic, hypoketotic encephalopathy precipitated by stressors with potential neurologic injury with seizures and progressive hypertrophic cardiomyopathy and limb-girdle myopathy. This disorder is reversible if recognized early and treatable with lifelong high dose oral Cn supplementation (100 mg/kg/day divided tid or qid) with the potential for a good quality of life, provided there have been no episodes of neurologic injury arising from hypoketotic hypoglycemia. During acute metabolic crises precipitated by infection, higher amounts of Cn may be required. The classic biochemical marker is extremely low serum total and free Cn concentrations (< 5 % of normal controls) with a normal esterified fraction and a marked decrease in renal tubular reabsorption of Cn. Institution of L-Cn from birth in infants with biallelic pathogenic variants in SLC22A5 can prevent development of the clinical phenotype. There have been milder, later-onset cases with ADHD. Infants are detectable on NBS though there have been cases of false negatives and false positives related to maternal Cn stores. Elevated renal fractional excretion of Cn appears to be more sensitive and specific. Cn physiology and metabolism will be reviewed.

Dr. Samantha Marin
Division of Neurology, Dept. of Pediatrics, The Health Sciences Centre Winnipeg, University of Manitoba, 
smarin2@hsc.mb.ca
Update on Pyridoxine-dependent epilepsy
Description of talk.Pyridoxine-Dependent Epilepsy (PDE) is a rare cause of early onset seizures, typically with intractable epilepsy in the first few weeks to months of life, with variable seizure types, often accompanied by neonatal or infantile encephalopathy. Atypical forms present with later onset (<3 years) seizures that may initially respond to anti-seizure medications and subsequently become medication resistant. Diagnosis depends on clinical recognition with a trial of pyridoxine, supportive laboratory findings (elevated plasma and urinary alpha-aminoadipic semialdehyde, elevated CSF levels of pipecolic acid, and analysis of CSF monoamine metabolites for two peaks of unknown identity) followed by confirmation with genetic testing of the ALDH7A1 gene. Treatment consists of pyridoxine supplementation according to published clinical practice guidelines form the International PDE Consortium. Alternative management strategies, including dietary modification with lysine-restricted diets and L-arginine supplementation have been investigated. The differential diagnosis includes other forms of pyridoxine-responsive seizures including pyridoxine dependent epilepsy due to pathogenic variants in PLPBP, pyridoxal phosphate dependent epilepsy due to pathogenic variants in PNPO (requiring supplementation with pyidoxal-5-phospate) and folinic acid responsive seizures (FARS), which are allelic with PDE.

Dr. Suvasini Sharma
Division of Neurology, Dept. of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India
Sharma.suvasini@gmail.com
Update on Biotinidase and Holocarboxylase synthetase deficiency
Holocarboxylase synthetase deficiency and biotinidase deficiency are rare autosomal recessive inherited neurometabolic disorders which are treatable with biotin supplementation. Hence it is imperative that pediatricians and child neurologists recognize these conditions as early and appropriate treatments can improve the neurodevelopmental outcomes. Holocarboxylase synthetase catalyzes the biotinylation of four biotin-dependent carboxylases; pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase, and methylcrotonyl-CoA carboxylase. Clinical features poor feeding, respiratory distress, lethargy, vomiting, hypotonia, seizures, developmental delay, alopecia, and skin rash.Biotinidase deficiency presents in infancy with refractory seizures, hypotonia, developmental delay, alopecia and eczematous dermatitis. In older children, it can present with spastic paraparesis and even mimic neuromyelitis optica or multiple sclerosis. Other features which may be present include ataxia, sensorineural hearing loss, optic atrophy, stridor and hepatosplenomegaly. Elevated arterial lactate is commonly present. Treatment consists of supplementation with biotin and supportive care. As early supplementation with biotin can significantly improve neurological outcomes, biotinidase deficiency is a component of newborn screening program in many countries.

Dr. Brahim Tabarki Melaiki
Division of Pediatric Neurology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia and University of Sousse, Tunisia
btabarki@hotmail.com
Update in diagnosis and treatment of Biotin-thiamine-responsive basal ganglia disease
Biotin–thiamine-responsive basal ganglia disease (BTBGD) is a relatively frequent panethnic disease. It is a treatable autosomal recessive neurometabolic disorder caused by pathogenic variants in the SLC19A3 gene. The SLC19A3 gene encodes the THTR2 (thiamine transporter 2), which helps to absorb vitamins from the intestines, its reclamation from renal tubules, and plays a key role in its uptake into the cells. Thiamine is a crucial cofactor involved in the maintenance of carbohydrate metabolism and participates in multiple cellular metabolic processes within the cytosol, mitochondria, and peroxisomes. BTBGD is characterized by episodic encephalopathy preceded by febrile illness, seizures, ataxia, dysphagia, and ophthalmoplegia, eventually leading to coma, and even death if not treated on time. Although onset is usually in childhood, it may range from the newborn period to adulthood. Brain MRI shows characteristic basal ganglia lesions and necrosis in the putamen and caudate nucleus. Free thiamine in CSF is a potential biomarker for diagnosis, and definitive diagnosis is made by analysis of the SLC19A3 gene. Early diagnosis and treatment are crucial. Treatment of BTBGD is based on the combination of thiamine and biotin. This regimen improves clinical outcome and survival, and prevents further metabolic crisis. In this session, we will discuss the metabolic pathways, epidemiology, clinical features, neuroradiological findings, genetic defects, and treatment of BTBGD.