SORDD: mutation frequency and phenotype in predominantly axonal Charcot-Marie-Tooth disease of undefined genetic cause.

Pathogenic, biallelic variants in SORD were identified in 2020 as a novel cause for autosomal-recessive Charcot-Marie-Tooth disease (CMT) type 2, an inherited neuropathy. SORD codes for the enzyme sorbitol dehydrogenase. Loss of this enzyme's activity leads to an increase of sorbitol in serum. We retrospectively screened 166 patients with axonal neuropathy (predominantly CMT type 2, but including intermediate form of CMT and distal hereditary motor neuropathy (dHMN)) without identified genetic etiology for SORD mutations at a single large German neuromuscular center. Clinical and electrophysiology exam findings were analyzed for genotype-phenotype correlation. Five patients of the total cohort of 166 patients harbored pathogenic variants in SORD (3%). The homozygous frameshift variant c.757delG (p.Ala253Glnfs*27) was the most common (4/5). One additional case carried this variant on one allele only and an additional pathogenic missense variant c.458C > A (p.Ala153Asp) on the other allele. Age of onset ranged from early infancy to mid-twenties, and phenotypes comprised axonal CMT (4) and dHMN (1). Our findings strengthen the importance of screening for pathogenic variants in SORD, especially in patients with genetically unconfirmed axonal neuropathy, especially CMT type 2 and dHMN.

Anaplerotic Therapy Using Triheptanoin in Two Brothers Suffering from Aconitase 2 Deficiency.

Citric acid cycle deficiencies are extremely rare due to their central role in energy metabolism. The ACO2 gene encodes the mitochondrial isoform of aconitase (aconitase 2), the second enzyme of the citric acid cycle. Approximately 100 patients with aconitase 2 deficiency have been reported with a variety of symptoms, including intellectual disability, hypotonia, optic nerve atrophy, cortical atrophy, cerebellar atrophy, and seizures. In this study, a homozygous deletion in the ACO2 gene in two brothers with reduced aconitase 2 activity in fibroblasts has been described with symptoms including truncal hypotonia, optic atrophy, hyperopia, astigmatism, and cerebellar atrophy. In an in vivo trial, triheptanoin was used to bypass the defective aconitase 2 and fill up the citric acid cycle. Motor abilities in both patients improved.

Mitochondrial DNA mutations in Medulloblastoma.

To date, several studies on genomic events underlying medulloblastoma (MB) biology have expanded our understanding of this tumour entity and led to its division into four groups-WNT, SHH, group 3 (G3) and group 4 (G4). However, there is little information about the relevance of pathogenic mitochondrial DNA (mtDNA) mutations and their consequences across these. In this report, we describe the case of a female patient with MB and a mitochondriopathy, followed by a study of mtDNA variants in MB groups. After being diagnosed with G4 MB, the index patient was treated in line with the HIT 2000 protocol with no indications of relapse after five years. Long-term side effects of treatment were complemented by additional neurological symptoms and elevated lactate levels ten years later, resulting in suspected mitochondrial disease. This was confirmed by identifying a mutation in the MT-TS1 gene which appeared homoplasmic in patient tissue and heteroplasmic in the patient's mother. Motivated by this case, we explored mtDNA mutations across 444 patients from ICGC and HIT cohorts. While there was no statistically significant enrichment of mutations in one MB group, both cohorts encompassed a small group of patients harbouring potentially deleterious mtDNA variants. The case presented here highlights the possible similarities between sequelae caused by MB treatment and neurological symptoms of mitochondrial dysfunction, which may apply to patients across all MB groups. In the context of the current advances in characterising and interpreting mtDNA aberrations, recognising affected patients could enhance our future knowledge regarding the mutations' impact on carcinogenesis and cancer treatment.

A mutation in the neonatal isoform of SCN2A causes neonatal-onset epilepsy.

SCN2A (sodium channel 2A) encodes the Nav1.2 channel protein in excitatory neurons in the brain. Nav1.2 is a critical voltage-gated sodium channel of the central nervous system. Mutations in SCN2A are responsible for a broad phenotypic spectrum ranging from autism and developmental delay to severe encephalopathy with neonatal or early infantile onset. SCN2A can be spliced into two different isoforms, a neonatal (6N) and an adult (6A) form. After birth, there is an equal or higher amount of the 6N isoform, protecting the brain from the increased neuronal excitability of the infantile brain. During postnatal development, 6N is gradually replaced by 6A. In an infant carrying the novel SCN2A mutation c.643G > A (p.Ala215Thr) only in the neonatal transcript, seizures started immediately after birth. The clinical presentation evolved from a burst-suppression pattern with 30-50 tonic seizures per day to hypsarrhythmia. The first exome analysis, focusing only on common transcripts, missed the diagnosis and delayed early therapy. A reevaluation including all transcripts revealed the SCN2A variant.

Uridine Treatment of the First Known Case of SLC25A36 Deficiency.

SLC25A36 is a pyrimidine nucleotide carrier playing an important role in maintaining mitochondrial biogenesis. Deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction. In human beings, diseases triggered by SLC25A36 mutations have not been described yet. We report the first known case of SLC25A36 deficiency in a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. Whole exome analysis identified the homozygous mutation c.803dupT, p.Ser269llefs*35 in the SLC25A36 gene. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with oral uridine led to an improvement of thyroid function and obstipation, increase of growth and developmental progress. Our findings suggest an important role of SLC25A36 in hormonal regulations and oral uridine as a safe and effective treatment.

Tubulin Folding Cofactor D Deficiency: Missing the Diagnosis With Whole Exome Sequencing.

Two siblings with an early onset of a neurodegenerative disease were presented with muscular hypotonia, secondary microcephaly, and severe developmental delay. Seizures were refractory to treatment but could be controlled with a ketogenic diet. Over the course of 5 years, whole exome sequencing (WES) was performed twice in both children. The first time the diagnosis was missed. The next one revealed compound heterozygous mutations in the gene coding for the tubulin folding cofactor D. Technical improvements in WES mandated a new investigation after a few years in children where the diagnosis has not been found.

Translational balancing questioned: Unaltered glycosylation during disulfiram treatment in mannosyl-oligosaccharide alpha-1,2-mannnosidase-congenital disorders of glycosylation (MAN1B1-CDG).

MAN1B1-CDG is a multisystem disorder caused by mutations in MAN1B1, encoding the endoplasmic reticulum mannosyl-oligosaccharide alpha-1,2-mannnosidase. A defect leads to dysfunction within the degradation of misfolded glycoproteins. We present two additional patients with MAN1B1-CDG and a resulting defect in endoplasmic reticulum-associated protein degradation. One patient (P2) is carrying the previously undescribed p.E663K mutation. A therapeutic trial in patient 1 (P1) using disulfiram with the rationale to generate an attenuation of translation and thus a balanced, restored ER glycoprotein synthesis failed. No improvement of the transferrin glycosylation profile was seen.

3-Hydroxyisobutyrate dehydrogenase (HIBADH) deficiency-A novel disorder of valine metabolism.

3-Hydroxyisobutyric acid (3HiB) is an intermediate in the degradation of the branched-chain amino acid valine. Disorders in valine degradation can lead to 3HiB accumulation and its excretion in the urine. This article describes the first two patients with a new metabolic disorder, 3-hydroxyisobutyrate dehydrogenase (HIBADH) deficiency, its phenotype and its treatment with a low-valine diet. The detected mutation in the HIBADH gene leads to nonsense-mediated mRNA decay of the mutant allele and to a complete loss-of-function of the enzyme. Under strict adherence to a low-valine diet a rapid decrease of 3HiB excretion in the urine was observed. Due to limited patient numbers and intrafamilial differences in phenotype with one affected and one unaffected individual, the clinical phenotype of HIBADH deficiency needs further evaluation.

Severe Form of ßIV-Spectrin Deficiency With Mitochondrial Dysfunction and Cardiomyopathy-A Case Report.

ßIV-spectrin is a protein of the spectrin family which is involved in the organization of the cytoskeleton structure and is found in high quantity in the axon initial segment and the nodes of Ranvier. Together with ankyrin G, ßIV-spectrin is responsible for the clustering of KCNQ2/3-potassium channels and NaV-sodium channels. Loss or reduction of ßIV-spectrin causes a destabilization of the cytoskeleton and an impairment in the generation of the action potential, which leads to neuronal degeneration. Furthermore, ßIV-spectrin has been described to play an important role in the maintenance of the neuronal polarity and of the diffusion barrier. ßIV-spectrin is also located in the heart where it takes an important part in the structural organization of ion channels and has also been described to participate in cell signaling pathways through binding of transcription factors. We describe two patients with a severe form of ßIV-spectrin deficiency. Whole-exome sequencing revealed the homozygous stop mutation c.6016C>T (p.R2006*) in the SPTBN4 gene. The phenotype of these patients is characterized by profound psychomotor developmental arrest, respiratory insufficiency and deafness. Additionally one of the patients presents with cardiomyopathy, optical nerve atrophy, and mitochondrial dysfunction. This is the first report of a severe form of ßIV-spectrin deficiency with hypertrophic cardiomyopathy and mitochondrial dysfunction.

TRAPγ-CDG shows asymmetric glycosylation and an effect on processing of proteins required in higher organisms.

Newly synthesised glycoproteins enter the rough endoplasmic reticulum through a translocation pore. The translocon associated protein (TRAP) complex is located close to the pore. In a patient with a homozygous start codon variant in TRAPγ (SSR3), absence of TRAPγ causes disruption of the TRAP complex, impairs protein translocation into the endoplasmic reticulum and affects transport, for example, into the brush-border membrane. Furthermore, we observed an unbalanced non-occupancy of N-glycosylation sites. The major clinical features are intrauterine growth retardation, facial dysmorphism, congenital diarrhoea, failure to thrive, pulmonary disease and severe psychomotor disability.