Shanti Balasubramaniam

Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5′-phosphate availability

We describe two neonates presenting with perinatal hypophosphatasia and severe epileptic encephalopathy resulting in death. Both had increased levels of urinary vanillactate, indicating functional deficiency of aromatic amino acid decarboxylase, a pyridoxal-5-phosphate (PLP)-dependent enzyme required for dopamine and serotonin biosynthesis. Clinical findings and results of subsequent metabolic investigations were consistent with secondary pyridoxine-deficient encephalopathy. These patients highlight the importance of tissue non-specific alkaline phosphatase in the neuronal PLP-dependent metabolism of neurotransmitters. In addition, the disturbance of PLP metabolism appears to underlie the predominant neurological presentation in our patients. We recommend the measurement of serum alkaline phosphatase (ALP) during the assessment of perinatal seizures.

Contiguous gene deletion syndrome in a female with ornithine transcarbamylase deficiency

OTC deficiency, a partially dominant X-linked trait, is the most frequent inborn error of the urea cycle. We describe a female patient with a contiguous gene deletion syndrome encompassing the OTC, DMD, RPGR, CYBB and XK genes, amongst others, only manifesting features of OTC deficiency. Molecular characterization was ascertained by MLPA and confirmed by CGH microarray, which revealed an 8.7 Mb deletion of the X-chromosome. Complete de novo deletion of the OTC gene led to a severe clinical phenotype in the proband. The application of high resolution molecular genetic techniques such as MLPA and array CGH, in mutation negative OTC cases allows the identification of chromosomal rearrangements, such as large deletions and provides information for accurate genetic counseling and prenatal diagnosis.

Inborn errors of pyrimidine metabolism: clinical update and therapy

Inborn errors involving enzymes essential for pyrimidine nucleotide metabolism have provided new insights into their fundamental physiological roles as vital constituents of nucleic acids as well as substrates of lipid and carbohydrate metabolism and in oxidative phosphorylation. Genetic aberrations of pyrimidine pathways lead to diverse clinical manifestations including neurological, immunological, haematological, renal impairments, adverse reactions to analogue therapy and association with malignancies. Maintenance of cellular nucleotides depends on the three aspects of metabolism of pyrimidines: de novo synthesis, catabolism and recycling of these metabolites. Of the ten recognised disorders of pyrimidine metabolism treatment is currently restricted to only two disorders: hereditary orotic aciduria (oral uridine therapy) and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; allogeneic hematopoetic stem cell transplant and enzyme replacement). The ubiquitous role that pyrimidine metabolism plays in human life highlights the importance of improving diagnostic evaluation in suggestive clinical settings, which will contribute to the elucidation of new defects, future development of novel drugs and therapeutic strategies. Limited awareness of the expanding phenotypic spectrum, with relatively recent descriptions of newer disorders, compounded by considerable genetic heterogeneity has often contributed to the delays in the diagnosis of this group of disorders. The lack of an easily recognisable, easily measurable end product, akin to uric acid in purine metabolism, has contributed to the under-recognition of these disorders.This review describes the currently known inborn errors of pyrimidine metabolism, their variable phenotypic presentations, established diagnostic methodology and recognised treatment options.

Treatment of Lesch-Nyhan disease with S-adenosylmethionine: Experience with five young Malaysians, including a girl

BACKGROUND Lesch-Nyhan disease (LND) is a rare X-linked recessive neurogenetic disorder caused by deficiency of the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT, EC 2.4.2.8) which is responsible for recycling purine bases into purine nucleotides. Affected individuals have hyperuricemia leading to gout and urolithiasis, accompanied by a characteristic severe neurobehavioural phenotype with compulsive self-mutilation, extrapyramidal motor disturbances and cognitive impairment. AIM For its theoretical therapeutic potential to replenish the brain purine nucleotide pool, oral supplementation with S-adenosylmethionine (SAMe) was trialed in 5 Malaysian children with LND, comprising 4 related Malay children from 2 families, including an LND girl, and a Chinese Malaysian boy. RESULTS Dramatic reductions of self-injury and aggressive behaviour, as well as a milder reduction of dystonia, were observed in all 5 patients. Other LND neurological symptoms did not improve during SAMe therapy. DISCUSSION Molecular mechanisms proposed for LND neuropathology include GTP depletion in the brain leading to impaired dopamine synthesis, dysfunction of G-protein-mediated signal transduction, and defective developmental programming of dopamine neurons. The improvement of our LND patients on SAMe, particularly the hallmark self-injurious behaviour, echoed clinical progress reported with another purine nucleotide depletion disorder, Arts Syndrome, but contrasted lack of benefit with the purine disorder adenylosuccinate lyase deficiency. This first report of a trial of SAMe therapy in LND children showed remarkably encouraging results that warrant larger studies.

Inborn errors of purine metabolism: clinical update and therapies

Inborn errors of purine metabolism exhibit broad neurological, immunological, haematological and renal manifestations. Limited awareness of the phenotypic spectrum, the recent descriptions of newer disorders and considerable genetic heterogeneity, have contributed to long diagnostic odysseys for affected individuals. These enzymes are widely but not ubiquitously distributed in human tissues and are crucial for synthesis of essential nucleotides, such as ATP, which form the basis of DNA and RNA, oxidative phosphorylation, signal transduction and a range of molecular synthetic processes. Depletion of nucleotides or accumulation of toxic intermediates contributes to the pathogenesis of these disorders. Maintenance of cellular nucleotides depends on the three aspects of metabolism of purines (and related pyrimidines): de novo synthesis, catabolism and recycling of these metabolites. At present, treatments for the clinically significant defects of the purine pathway are restricted: purine 5′-nucleotidase deficiency with uridine; familial juvenile hyperuricaemic nephropathy (FJHN), adenine phosphoribosyl transferase (APRT) deficiency, hypoxanthine phosphoribosyl transferase (HPRT) deficiency and phosphoribosyl-pyrophosphate synthetase superactivity (PRPS) with allopurinol; adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiencies have been treated by bone marrow transplantation (BMT), and ADA deficiency with enzyme replacement with polyethylene glycol (PEG)-ADA, or erythrocyte-encapsulated ADA; myeloadenylate deaminase (MADA) and adenylosuccinate lyase (ADSL) deficiencies have had trials of oral ribose; PRPS, HPRT and adenosine kinase (ADK) deficiencies with S-adenosylmethionine; and molybdenum cofactor deficiency of complementation group A (MOCODA) with cyclic pyranopterin monophosphate (cPMP). In this review we describe the known inborn errors of purine metabolism, their phenotypic presentations, established diagnostic methodology and recognised treatment options.

MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder.

Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285∗), c.247_250del (p.Asn83Hisfs∗4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.

Phenotypic Variation of TTC19- Deficient Mitochondrial Complex III Deficiency: A Case Report and Literature Review

Isolated mitochondrial respiratory chain complex III deficiency has been described in a heterogeneous group of clinical presentations in children and adults. It has been associated with mutations in MT‐CYB, the only mitochondrial DNA encoded subunit, as well as in nine nuclear genes described thus far: BCS1L, TTC19, UQCRB, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7, and UQCC3. BCS1L, TTC19, UQCC2, LYRM7, and UQCC3 are complex III assembly factors. We report on an 8‐year‐old girl born to consanguineous Iraqi parents presenting with slowly progressive encephalomyopathy, severe failure to thrive, significant delays in verbal and communicative skills and bilateral retinal cherry red spots on fundoscopy. SNP array identified multiple regions of homozygosity involving 7.5% of the genome. Mutations in the TTC19 gene are known to cause complex III deficiency and TTC19 was located within the regions of homozygosity. Sequencing of TTC19 revealed a homozygous nonsense mutation at exon 6 (c.937C > T; p.Q313X). We reviewed the phenotypes and genotypes of all 11 patients with TTC19 mutations leading to complex III deficiency (including our case). The consistent features noted are progressive neurodegeneration with Leigh‐like brain MRI abnormalities. Significant variability was observed however with the age of symptom onset and rate of disease progression. The bilateral retinal cherry red spots and failure to thrive observed in our patient are unique features, which have not been described, in previously reported patients with TTC19 mutations. Interestingly, all reported TTC19 mutations are nonsense mutations. The severity of clinical manifestations however does not specifically correlate with the residual complex III enzyme activities.

A mutation in MT-TW causes a tRNA processing defect and reduced mitochondrial function in a family with Leigh syndrome

Leigh syndrome (LS) is a progressive mitochondrial neurodegenerative disorder, whose symptoms most commonly include psychomotor delay with regression, lactic acidosis and a failure to thrive. Here we describe three siblings with LS, but with additional manifestations including hypertrophic cardiomyopathy, hepatosplenomegaly, cholestatic hepatitis, and seizures. All three affected siblings were found to be homoplasmic for an m. 5559A>G mutation in the T stem of the mitochondrial DNA-encoded MT-TW by next generation sequencing. The m.5559A>G mutation causes a reduction in the steady state levels of tRNA(Trp) and this decrease likely affects the stability of other mitochondrial RNAs in the patient fibroblasts. We observe accumulation of an unprocessed transcript containing tRNA(Trp), decreased de novo protein synthesis and consequently lowered steady state levels of mitochondrial DNA-encoded proteins that compromise mitochondrial respiration. Our results show that the m.5559A>G mutation at homoplasmic levels causes LS in association with severe multi-organ disease (LS-plus) as a consequence of dysfunctional mitochondrial RNA metabolism.

Unique presentation of cutis laxa with Leigh-like syndrome due to ECHS1 deficiency

Clinical finding of cutis laxa, characterized by wrinkled, redundant, sagging, nonelastic skin, is of growing significance due to its occurrence in several different inborn errors of metabolism (IEM). Metabolic cutis laxa results from Menkes syndrome, caused by a defect in the ATPase copper transporting alpha (ATP7A) gene; congenital disorders of glycosylation due to mutations in subunit 7 of the component of oligomeric Golgi (COG7)–congenital disorders of glycosylation (CDG) complex; combined disorder of N- and O-linked glycosylation, due to mutations in ATPase H+ transporting V0 subunit a2 (ATP6VOA2) gene; pyrroline-5-carboxylate reductase 1 deficiency; pyrroline-5-carboxylate synthase deficiency; macrocephaly, alopecia, cutis laxa, and scoliosis (MACS) syndrome, due to Ras and Rab interactor 2 (RIN2) mutations; transaldolase deficiency caused by mutations in the transaldolase 1 (TALDO1) gene; Gerodermia osteodysplastica due to mutations in the golgin, RAB6-interacting (GORAB or SCYL1BP1) gene; and mitogen-activated pathway (MAP) kinase defects, caused by mutations in several genes [protein tyrosine phosphatase, non-receptor-type 11 (PTPN11), RAF, NF, HRas proto-oncogene, GTPase (HRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), MEK1/2, KRAS proto-oncogene, GTPase (KRAS), SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2), leucine rich repeat scaffold protein (SHOC2), NRAS proto-oncogene, GTPase (NRAS), and Raf-1 proto-oncogene, serine/threonine kinase (RAF1)], which regulate the Ras-MAPK cascade. Here, we further expand the list of inborn errors of metabolism associated with cutis laxa by describing the clinical presentation of a 17-month-old girl with Leigh-like syndrome due to enoyl coenzyme A hydratase, short chain, 1, mitochondria (ECHS1) deficiency, a mitochondrial matrix enzyme that catalyzes the second step of the beta-oxidation spiral of fatty acids and plays an important role in amino acid catabolism, particularly valine.

Overcoming the barriers to diagnosis of Morquio A syndrome

BackgroundMorquio A syndrome is an autosomal recessive lysosomal storage disease often resulting in life-threatening complications. Early recognition and proficient diagnosis is imperative to facilitate prompt treatment and prevention of clinical complications.MethodsExperts in Asia Pacific reviewed medical records focusing on presenting signs and symptoms leading to a diagnosis of Morquio A syndrome.ResultsEighteen patients (77% female) had a mean (median; min, max) age of 77.1 (42.0; 0.0, 540.0) months at symptom onset, 78.9 (42.0; 4.5, 540.0) months at presentation and 113.8 (60.0; 7.0, 540.0) months at diagnosis. Orthopedic surgeons and pediatricians were most frequently consulted pre-diagnosis while clinical geneticists/metabolic specialists most frequently made the diagnosis. Delayed diagnoses were due to atypical symptoms for 5 patients (28%), while 4 patients (22%) experienced each of subtle symptoms, symptoms commonly associated with other diseases, or false-negative urine glycosaminoglycan analysis. Two patients (11%) each experienced overgrowth within the first year of life. Two patients with Morquio A syndrome (11%) were diagnosed with craniosynostosis and 1 (6%) for each of Legg-Calvé-Perthes disease, Leri-Weill syndrome, and pseudoachondroplasia. Early radiographic features of Morquio A syndrome led to more efficient diagnosis.ConclusionsIncreased awareness of clinical symptomology overlapping with Morquio A syndrome is essential. Clinicians encountering patients with certain skeletal dysplasia should consider Morquio A syndrome in their differential diagnosis. Atypical or subtle symptoms should not eliminate Morquio A syndrome from the differential diagnosis, especially for patients who may have non-classical phenotype of Morquio A syndrome.