Three Afghani siblings with a novel homozygous variant and further delineation of the clinical features of METTL5 related intellectual disability syndrome.

BACKGROUND: METTL5 gene is one of the members of methyltransferase superfamily and biallelic variants cause intellectual disability syndrome (ID) with microcephaly. This article reports three new cases with METTL5 related ID syndrome in a consanguineous family. CASE: Afghanistan descent family was affected by a novel homozygous c.362A > G (p.Asp121Gly) METTL5 gene variant. This variant is predicted to be `pathogenic` by multiple in-silico tools. Patients had dysmorphic and neurodevelopmental features including intellectual disability, microcephaly, poor/absent speech, delayed walking, aggressive behavior, large/posteriorly rotated ears, broad nasal base and short stature, which seem to be the cardinal findings of the designated syndrome. CONCLUSIONS: While the data reported in these individuals indicate characteristic clinical features of METTL5 related ID syndrome, further investigations and study of additional cases are needed to improve the understanding of disease pathogenesis, and management.

Carbonic anhydrase VA deficiency: a very rare case of hyperammonemic encephalopathy.

Objectives Carbonic anhydrase VA (CAVA) deficiency is a rare autosomal recessive inborn error of metabolism that leads to acute metabolic crises, especially in the neonatal or infantile period. It is caused by a deficiency of the enzyme CAVA, which is encoded by the CA5A gene. Case presentation Fifteen patients with homozygous pathogenic CA5A mutations involving 10 different lesions have been reported in the literature up to date. Main clinical and biochemical features of CAVA deficiency include lethargy, hyperammonemic encephalopathy, metabolic acidosis, elevated lactate and hypoglycemia. In most patients reported so far, a single metabolic decompensation attack has been reported, and they have remained stable thereafter with no further crisis. Conclusions We report the 16th case of CAVA deficiency, who was diagnosed by whole-exome sequencing and showed a typical course of the disease with normal development at 18 months.

Successful PGD for late infantile neuronal ceroid lipofuscinosis achieved by combined chromosome and TPP1 gene analysis.

Late infantile neuronal ceroid lipofuscinosis (NCL-2) is a severe debilitating autosomal recessive disease caused by mutations in TPP1. There are no effective treatments, resulting in early childhood death. A couple with two affected children presented for reproductive genetic counselling and chose to undertake IVF and preimplantation genetic diagnosis (PGD) to avoid the possibility of another affected child. However, DNA testing revealed only one mutation in the proband inherited from mother. Linkage analysis identified five informative linked short tandem repeat markers to aid the genetic diagnosis. Following IVF, five cleavage-stage embryos were biopsied and blastomeres were first subjected to whole-genome amplification, then a series of down-stream molecular genetic analyses to diagnose TPP1 genotype and finally array comparative genomic hybridization (CGH) to assess the chromosomal ploidy of each embryo. Two unaffected euploid embryos were identified for transfer. One was transferred on day 5 resulting in an ongoing pregnancy. Confirmatory prenatal diagnosis by amniocentesis showed concordance of the embryo and fetal diagnosis. As far as is known, this is the first successful report of PGD for NCL-2 using double-factor PGD with simultaneous single-gene testing and array CGH to identify an unaffected and chromosomally normal embryo for transfer.