The Challenge of Severe Acute Malnutrition in Inborn Errors of Metabolism: Does Medical Food Alone Suffice?

Glutaric aciduria type 1 (GA-1) is a treatable inborn error of metabolism caused by glutaryl-CoA dehydrogenase deficiency. This enzyme deficiency leads to accumulation of glutaric acid, 3-hydroxy glutaric acid, and glutaconic acid which are potentially neurotoxic. Patients with GA-1 have characteristic clinical and neuroimaging features that help us to clinch the diagnosis. Early diagnosis by newborn screening helps us to prevent the motor problems such as dystonia and spasticity. Treatment includes low-protein diet along with carnitine supplementation which may lead to deficiency of essential amino acids and hence malnutrition. Managing malnutrition in a child with inborn errors of metabolism (IEM) is challenging. Here, we describe a patient, a case of GA-1 on medical food, presenting with severe acute malnutrition, who improved with a combination of medical and home-made foods along with lysine-free, tryptophan-reduced amino acid supplements.

Peripheral Neuropathy in Children With Chronic Kidney Disease: Are We Looking Enough?

Background: Peripheral neuropathy in chronic kidney disease (CKD) is the most common neurological complication. We aimed to look at the prevalence and patterns of neuropathy in children with CKD. Methods: This cross-sectional study was conducted over 1 year in children with CKD, stage III and above. Nerve conduction studies (NCS) were performed as per standard protocols using surface electrodes on the muscles and by supramaximal stimulation of the corresponding nerves. Presence of electrophysiological abnormalities in the absence of clinical symptoms or signs was considered as subclinical neuropathy. Results: Nearly 45 children were evaluated. The majority were males (n = 39, 86.7%). The mean age was 7.9 ± 3 years (range 2-14). The mean estimated glomerular filtration rate (GFR) at enrolment was 23.3 ± 14.6 mL/min/1.73 m2 (range 5-67). The majority of children were in stage III (n = 19, 42%), followed by stages V (n = 15, 33%) and IV (n = 11, 25%). There was no evidence of clinical neuropathy; 13 children (29%) showed subclinical neuropathy. All the nerves had an axonal pattern of involvement. Motor polyneuropathy was most common type of peripheral neuropathy. The commonest nerves involved were tibial and common peroneal nerves. There were no biochemical or clinical predictors of neuropathy in our cohort. Conclusion: The prevalence of subclinical neuropathy is high in children with CKD, stage III and above. Axonal motor polyneuropathy is the predominant pattern. Electrophysiological assessment of nerve function should be routinely done in children with advanced stages of CKD to prevent chronic complications.

Identification of novel pathogenic variants in the GCDH gene and assessment of neurodevelopmental outcomes in 24 children with glutaric aciduria type 1.

AIM: To evaluate the pathogenic variants in GCDH gene and to assess the neurodevelopmental outcomes in children with Glutaric aciduria type 1 (GA-1). METHOD: Cross-sectional observational study between January 2019 and June 2020 in consecutive North Indian children with a clinical and biochemical suspicion of GA-1. Variants in the coding regions of GCDH gene were identified through Sanger sequencing. Neurodevelopmental and quality of life assessment was done using standardized scales. RESULTS: 24 children with GA-1 were identified. The median age at diagnosis was 12 months and the median delay in diagnosis was 3 months. Genetic analysis was done in 14 cases. It revealed 12 variants (11 missense and one nonsense) from 13 patients. Most of the pathogenic variants were in exon 9 and exon 5. Three novel variants were identified in three patients: two missense variants c.169G > A (p.Glu57Lys), c.1048T > C (p.Cys350Arg) and one nonsense variant c.331C > T (p.Lys111Ter). On neurodevelopmental assessment, majority of children with GA-1 were non ambulatory (62.5%), had limited hand skills (58.3%) and impaired communication (58.3%). Overall, poor global development was noted in 43.7%. A pre-existing developmental delay was significantly associated with impaired communication skills (p = 0.03), and the number of episodes of encephalopathy were significantly associated with impaired gross motor skill (p = 0.02). Presence of encephalopathy was significantly associated with poor performance in social emotional (p = 0.01) and cognitive (p = 0.03) domains of Developmental Profile-III scale and development of severe dystonia (p = 0.01). CONCLUSION: Our findings highlight the clinical, biochemical, radiological and genetic spectrum of GA-1 in children in North India and report the presence of novel pathogenic variations.

PPP2R5D-Related Neurodevelopmental Disorder or Developmental and Epileptic Encephalopathy?: A Novel Phenotypic Description and Review of Published Cases.

BACKGROUND: Protein phosphatase 2 regulatory subunit B' delta (PPP2R5D)-related neurodevelopmental disorder is caused by pathogenic variations in the PPP2R5D gene, product of which is involved in dephosphorylation. This is a rare disorder with description limited to case reports. Its phenotypic spectrum has expanded over the last decade. METHODS: We report a child with a developmental and epileptic encephalopathy phenotype with a pathogenic PPP2R5D variant. This phenotype has not been previously reported. We also reviewed the previously published reports of patients with this disorder. RESULTS: Including the index child, 28 cases (15 girls) were identified from nine relevant research items for analysis. All patients had developmental delay. History of seizures was observed in seven patients while macrocephaly was seen in nearly 80% of patients. Nonneurological manifestations were observed in 13 patients with the most common one being ophthalmological manifestations. The most common genetic variation was c.G592A (p.E198K). The common phenotypic associations of this variation were developmental delay, macrocephaly (11/15), and epilepsy (6/15). CONCLUSION: PPP2R5D gene variations should be suspected in children with developmental delay, autistic features, macrocephaly with or without epilepsy in the absence of any clear etiology. Dysmorphic features might provide a diagnostic clue. DEE phenotype may also be the presenting feature and might be an underreported entity.

Metabolic epilepsy in hyperprolinemia type II due to a novel nonsense ALDH4A1 gene variant.

Hyperprolinemia type II (HPII) is a rare autosomal recessive disorder of proline degradation pathway due to deficiency of delta-1-pyrroline-5-carboxylate dehydrogenase. Pathogenic variants in the ALDH4A1 gene are responsible for this disorder. We here describe an 11-month-old infant with recurrent seizures refractory to multiple antiepileptic drugs. She was hospitalized in view of acute-onset encephalopathy, exacerbation of generalized seizures following an upper respiratory infection. Laboratory investigation revealed significantly elevated proline levels in dried blood spots. DNA sample of the child was subjected to a targeted next-generation sequencing gene panel for hyperprolinemias. We detected a novel nonsense homozygous variant in the ALDH4A1 gene in the child and the heterozygous variant of the same in both the parents. Based on the location of the variant i.e. in the last exon, truncated protein is expected to be expressed by skipping nonsense-mediated decay and such point-nonsense variants could be an ideal target for readthrough drugs to correct genetic defects.

Autopsy of a child with Spinal muscular atrophy Type I (Werdnig-Hoffmann disease).

Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder which encompasses a large group of genetic disorders characterized by slowly progressive degeneration of lower motor neurons. The mutation is seen in the SMN1 gene mapped on chromosome 5. Depending on the age of the onset and the degree of severity, SMA has three subtypes. We discuss the autopsy findings in a case of Type 1 SMA also known by the name Werdnig-Hoffmann disease, to highlight the primary changes in the spinal cord, and skeletal muscle with association changes in the liver and terminal respiratory complications.

Autopsy of a child with Spinal muscular atrophy Type I (Werdnig-Hoffmann disease)

Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder which encompasses a large group of genetic disorders characterized by slowly progressive degeneration of lower motor neurons. The mutation is seen in the SMN1 gene mapped on chromosome 5. Depending on the age of the onset and the degree of severity, SMA has three subtypes. We discuss the autopsy findings in a case of Type 1 SMA also known by the name Werdnig-Hoffmann disease, to highlight the primary changes in the spinal cord, and skeletal muscle with association changes in the liver and terminal respiratory complications.