Hindi Al-Hindi

ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder

Background There are numerous nuclear genes that cause mitochondrial disorders and clinically and genetically heterogeneous disorders whose aetiology often remains unsolved. In this study, we aim to investigate an autosomal recessive syndrome causing leukodystrophy and neuroregression. We studied six patients from five unrelated consanguineous families. Methods Patients underwent full neurological, radiological, genetic, metabolic and dysmorphological examinations. Exome sequencing coupled with autozygosity mapping, Sanger sequencing, microsatellite haplotyping, standard and molecular karyotyping and whole mitochondrial DNA sequencing were used to identify the genetic cause of the syndrome. Immunohistochemistry, transmission electron microscopy, confocal microscopy, dipstick assays, quantitative PCR, reverse transcription PCR and quantitative reverse transcription PCR were performed on different tissue samples from the patients. Results We identified a homoallelic missense founder mutation in ISCA2 leading to mitochondrial depletion and reduced complex I activity as well as decreased ISCA2, ISCA1 and IBA57 expression in fibroblasts. MRI indicated similar white matter abnormalities in the patients. Histological examination of the skeletal muscle showed mild to moderate variation in myofibre size and the presence of many randomly distributed atrophic fibres. Conclusions Our data demonstrate that ISCA2 deficiency leads to a hereditary mitochondrial neurodegenerative white matter disease in infancy.

A novel deletion of the MEN1 gene in a large family of multiple endocrine neoplasia type 1 (MEN1) with aggressive phenotype

Context  The MEN1 syndrome is associated with parathyroid, pancreatic and pituitary tumours and is caused by mutations in the MEN1 gene. In general, there is no genotype–phenotype correlation.

Vici syndrome associated with unilateral lung hypoplasia and myopathy.

Vici Syndrome Associated With Unilateral Lung Hypoplasia and Myopathy Mohammed Al-Owain,* Amal Al-Hashem, Mohammed Al-Muhaizea, Hani Humaidan, Hindi Al-Hindi, Iftetah Al-Homoud, and Ibrahim Al-Mogarri Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Clinical and biochemical features associated with BCS1L mutation

Our study describes a novel phenotype in a series of nine Saudi patients with lactic acidosis, from four consanguineous families three of which are related. Detailed genetic studies including linkage, homozygosity mapping and targeted sequencing identified a causative mutation in the BCS1L gene. All affected members of the families have an identical mutation in this gene, mutations of which are recognized causes of Björnstad syndrome, GRACILE syndrome and a syndrome of neonatal tubulopathy, encephalopathy, and liver failure (MIM 606104) leading to isolated mitochondrial respiratory chain complex III deficiency. Here we report the appearance of a novel behavioral (five patients) and psychiatric (two patients) phenotype associated with a p.Gly129Arg BCS1L mutation, differing from the phenotype in a previously reported singleton patient with this mutation. The psychiatric symptoms emanated after childhood, initially as hypomania later evolving into intermittent psychosis. Neuroradiological findings included subtle white matter abnormalities, whilst muscle histopathology and respiratory chain studies confirmed respiratory chain dysfunction. The variable neuro-psychiatric manifestations and cortical visual dysfunction are most unusual and not reported associated with other BCS1L mutations. This report emphasizes the clinical heterogeneity associated with the mutation in BCS1L gene, even within the same family and we recommend that defects in this gene should be considered in the differential diagnosis of lactic acidosis with variable involvement of different organs.

Comparison of differentiated thyroid cancer in children and adolescents (≤20 years) with young adults

Age is a major prognostic factor in differentiated thyroid cancer (DTC). It is not clear if paediatric DTC has a different histopathological profile and outcome than DTC in adult patients <45 years of age.

Clinical and pathological heterogeneity of a congenital disorder of glycosylation manifesting as a myasthenic/myopathic syndrome.

Congenital disorders of glycosylation are often associated with muscle weakness in apparent isolation or as part of a multi-systemic disorder. We report here the clinical and pathological features resulting from a homozygous mutation of ALG2 in an extended family. Phenotypic heterogeneity is observed among the small cohort of patients reported to date and is highlighted by our study. Linkage analysis, homozygozity mapping and whole exome sequencing followed clinical and pathological characterization of patients who presented with a congenital limb girdle pattern of weakness with no ocular or bulbar involvement. Nerve stimulation studies were consistent with a congenital myasthenic syndrome. Severity and progression of disease was variable. Muscle biopsies showed myopathic features, ragged red fibers and a sub-sarcolemmal accumulation of structurally normal mitochondria. Whole exome sequencing revealed an indel mutation c.214_224delGGGGACTGGCTdelinsAGTCCCCG, p.72_75delGDWLinsSPR in exon 1 of ALG2. Mutation of ALG2 manifested as a limb girdle pattern of muscle weakness with defects at both the neuromuscular junction and sarcomere. In addition the accumulation and distribution of mitochondria in the diseased muscle and the presence of ragged red fibers were supportive of a mitochondrial myopathy. ALG2 mutation results in a heterogeneous phenotype and care should be taken in categorization and treatment of these patients.

Clinical and genetic features of anoctaminopathy in Saudi Arabia

Objectives: Characterization of the phenotypic, pathological, radiological, and genetic findings in 2 Saudi Arabian families with anoctaminopathies, and limb girdle muscular dystrophy type 2L (LGMD2L). Methods: Over a 2-year period from December 2010 to January 2013, the clinical presentations were analyzed and all genes responsible for limb girdle muscular dystrophy (LGMD) were screened in families seen at King Faisal Specialist Hospital and Research Centre, a tertiary care hospital in Riyadh, Saudi Arabia. Out of 66 families with LGMD, we identified 2 families (3.1%) with anoctaminopathy, ANO5 muscular dystrophy. Results: In the first case, a man presented with asymmetrical calves’ muscles weakness and atrophy, which was first noted at age 39. The creatinine kinase (CK) level was >20x normal, muscle biopsy showed necrotizing myopathic changes, and an MRI of the legs showed fatty-tissue replacement to muscle tissue with volume loss involving the gastrocnemius and soleus muscles in an asymmetrical fashion. Minimal disease progression was noted over 18 years of follow up. Exercise induced recurrent rhabdomyolysis was noted over the last 2 years. A novel ANO5 gene mutation (Arg58Trp) was found. In the second family, a male presented at the age of 41 with asymptomatic hyperCkemia and intermittent dyspnea. Over 10 years follow up, he became disabled with muscle cramps, rhabdomyolysis, myoglobinurea, and difficulty ambulating. Muscle biopsy showed necrotizing myopathy and perivascular and interstitial amyloid deposit in skeletal muscle. A homozygous deletion of 11.9 Kb encompassing exon 13 to exon 17 was found in the ANO5 gene. Full cardiac investigations were normal in both patients. Conclusion: The prevalence of LGMD2L is approximately 3.1% in a Saudi Arabian native LGMD cohort. Slowly progressive, late onset, and asymmetrical weakness was the salient features in these 2 families. The genetic findings were novel and will add to the spectrum of ANO5 known mutations.

Absence of EIF1AX, PPM1D, and CHEK2 mutations reported in Thyroid Cancer Genome Atlas (TCGA) in a large series of thyroid cancer

IntroductionThe Thyroid Cancer Genome Atlas (TCGA) was a major project that significantly clarified the key underlying genetic aberrations in papillary thyroid cancer. It confirmed the previously known somatic mutations and gene fusions and disclosed additional genetic alterations that were previously unknown. Among the most significant novel genetic mutations were those in EIF1AX, PPM1D, and CHEK2.ObjectivesWe sought to determine the rates of these novel genetic alterations in a large sample of our patients to test the prevalence, reproducibility, and significance of these findings.Patients and methodsWe studied thyroid cancer (TC) tumor tissues from 301 unselected patients using polymerase chain reaction (PCR) and direct Sanger sequencing. DNA was isolated from paraffin-embedded formalin-fixed tumor tissue. Exons and exon–intron boundaries harboring the previously reported mutations in TCGA were amplified using PCR and directly sequenced.ResultsWe found only one of the 301 tumors (0.3%) harboring A113_splice site mutation at the intron 5/exon 6 splice site of EIF1AX gene. Apart from this single mutation, none of the 301 tumors harbored any of the previously reported mutations in any of the three genes, EIF1AX, PPM1D, and CHEK2. A number of previously reported single nucleotide polymorphisms (SNP) were found in CHEK2, PPM1D but not in EIF1AX. These include CHEK2 SNPs, rs375130261, rs200928781, rs540635787, rs142763740, and rs202104749. The PPM1D SNPs rs771831676 and rs61757742 were present in 1.49% and 0.74%, respectively. Each of these SNPs was present in a heterozygous form in 100% of the tumors. An additional analysis of these samples for the most frequently reported mutations in DTC such as BRAFV600E, TERT promoter, and RAS showed a prevalence of 38.87% (117/301), 11.96% (36/301), and 7.64% (23/301), respectively.ConclusionsExcept for a rare A113_splice site mutation in EIF1AX, other recently described somatic mutations in EIF1AX, PPM1D, and CHEK2 were absent in this large series of patients with TC from a different racial group (Saudi Arabia). This might be related to the different techniques used (PCR and direct sequencing) or low density of the mutants. It might also reflect racial differences in the rate of these mutations.