Tribal Founder EMC1 Variant in 5 Kuwaiti Families Expands Phenotypic Spectrum of EMC1-Related Disorder.

Background and Objectives: The endoplasmic reticulum (ER) membrane protein complex is a conserved multisubunit transmembrane complex that enables energy-independent insertion of newly synthesized membrane proteins into ER membranes, mediating protein folding, phospholipid transfer from ER to mitochondria, and elimination of misfolded proteins. The first subunit of EMC (EMC1) is encoded by EMC1. Both monoallelic de novo and biallelic EMC1 variants have been identified to cause cerebellar atrophy, visual impairment, and psychomotor retardation (CAVIPMR) [OMIM #616875]. Eight families with biallelic EMC1 variants and CAVIPMR have been reported. Here, we describe 8 individuals from 5 Kuwaiti families from the same tribe, with the previously reported homozygous pathogenic missense EMC1 variant [c.245C>T:p.(Thr82Met)] and CAVIPMR. Methods: Proband exome sequencing was performed in 3 families, while targeted molecular testing for EMC1 [c.245C>T:p.(Thr82Met)] variant was performed in the other 2 families based on strong clinical suspicion and tribal origin. Sanger sequencing confirmed variant segregation with disease in all families. Results: We identified 8 individuals from 5 Kuwaiti families with the homozygous pathogenic EMC1 variant [c.245C>T:p.(Thr82Met)] previously reported in a Turkish family with CAVIPMR. The variant was absent from Kuwait Medical Genetic Center database, thus unlikely to represent a population founder allelic variant. The average age at symptom onset was 11 weeks, with all families reporting either visual abnormalities, hypotonia, and/or global developmental delay (GDD) as the presenting features. Shared clinical features included GDD (8/8), microcephaly (8/8), truncal hypotonia (8/8), visual impairment (7/7), and failure to thrive (7/7). Other common features included hyperreflexia (5/6; 83%), peripheral hypertonia (3/5; 60%), dysmorphism (3/6; 50%), epilepsy (4/8; 50%), and chorea (3/8; 36%). Brain imaging showed cerebellar atrophy in 4/7 (57%) and cerebral atrophy in 3/6 (50%) individuals. Discussion: The presence of exact biallelic homozygous EMC1 variant in 5 Kuwaiti families from the same tribe suggests a tribal founder allelic variant. The clinical features in this study are consistent with the phenotypic spectrum of EMC1-associated CAVIPMR in previous reports. The presence of chorea, first noted in this study, further expands the phenotypic spectrum. Our findings emphasize the importance of targeted EMC1 variant [c.245C>T:p.(Thr82Met)] testing for infants from affected tribe who present with visual impairment, GDD, and hypotonia.

Biotin-thiamine responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of cases in Kuwait with novel variants.

BACKGROUND: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive neurometabolic disorder that is caused by biallelic pathogenic SLC19A3 variants and is characterized by subacute encephalopathy associated with confusion, convulsions, dysphagia, dysarthria, or other neurological manifestations. METHODS: A retrospective review of the data registry in Kuwait Medical Genetics Center for all cases diagnosed clinically and radiographically and confirmed genetically with BTBGD. RESULTS: Twenty one cases from 13 different families were diagnosed with BTBGD in Kuwait. Most cases (86%) presented with confusion, dystonia, convulsions, or dysarthria, while three individuals were diagnosed pre-symptomatically during familial targeted genetic screening. Symptoms resolved completely within 2-week of treatment in two-thirds of the symptomatic cases but progressed in six of them to a variety of severe symptoms including severe cogwheel rigidity, dystonia and quadriparesis due to delayed presentation and management. Neuroradiological findings of the symptomatic cases revealed bilateral central changes in the basal ganglia. Two novel homozygous missense SLC19A3 variants were detected in a Kuwaiti and a Jordanian individuals, in addition to the previously reported Saudi founder homozygous variant, c.1264A > G; p.(Thr422Ala) in the remaining cases. Age of diagnosis ranged from newborn to 32 years, with a median age of 2-3 years. All cases are still alive receiving high doses of biotin and thiamine. CONCLUSION: This is the first study reporting the phenotypic and genotypic spectrum of 21 individuals with BTBGD in Kuwait and describing two novel SLC19A3 variants. BTBGD is a treatable neurometabolic disease that requires early recognition and treatment initiation. This study highlights the importance of performing targeted molecular testing of the founder variant in patients presenting with acute encephalopathy in the region.

LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes.

Defects of respiratory chain complex III (CIII) result in characteristic but rare mitochondrial disorders associated with distinct neuroradiological findings. The underlying molecular defects affecting mitochondrial CIII assembly factors are few and yet to be identified. LYRM7 assembly factor is required for proper CIII assembly where it acts as a chaperone for the Rieske iron-sulfur (UQCRFS1) protein in the mitochondrial matrix and stabilizing it. We present here the seventeenth individual with LYRM7-associated mitochondrial leukoencephalopathy harboring a previously reported rare pathogenic homozygous LYRM 7 variant, c.2T>C, (p.Met1?). Like previously reported individuals, our 5-year-old male proband presented with recurrent metabolic and lactic acidosis, encephalopathy, and fatigue. Further, he has additional, previously unreported features, including an acute stroke like episode with bilateral central blindness and optic neuropathy, recurrent hyperglycemia and hypertension associated with metabolic crisis. However, he has no signs of psychomotor regression. He has been stable clinically with residual left-sided reduced visual acuity and amblyopia, and no more metabolic crises for 2-year-period while on the mitochondrial cocktail. Although the reported brain MRI findings in other affected individuals are homogenous, it is slightly different in our index, revealing evidence of bilateral almost symmetric multifocal periventricular T2 hyperintensities with hyperintensities of the optic nerves, optic chiasm, and corona radiata but with no cavitation or cystic changes. This report describes new clinical and radiological findings of LYRM7-associated disease. The report also summarizes the clinical and molecular data of previously reported individuals describing the full phenotypic spectrum.

Early Diagnosis of Classic Homocystinuria in Kuwait through Newborn Screening: A 6-Year Experience.

Kuwait is a small Arabian Gulf country with a high rate of consanguinity and where a national newborn screening program was expanded in October 2014 to include a wide range of endocrine and metabolic disorders. A retrospective study conducted between January 2015 and December 2020 revealed a total of 304,086 newborns have been screened in Kuwait. Six newborns were diagnosed with classic homocystinuria with an incidence of 1:50,000, which is not as high as in Qatar but higher than the global incidence. Molecular testing for five of them has revealed three previously reported pathogenic variants in the CBS gene, c.969G>A, p.(Trp323Ter); c.982G>A, p.(Asp328Asn); and the Qatari founder variant c.1006C>T, p.(Arg336Cys). This is the first study to review the screening of newborns in Kuwait for classic homocystinuria, starting with the detection of elevated blood methionine and providing a follow-up strategy for positive results, including plasma total homocysteine and amino acid analyses. Further, we have demonstrated an increase in the specificity of the current newborn screening test for classic homocystinuria by including the methionine to phenylalanine ratio along with the elevated methionine blood levels in first-tier testing. Here, we provide evidence that the newborn screening in Kuwait has led to the early detection of classic homocystinuria cases and enabled the affected individuals to lead active and productive lives.

Are Histopathological Changes of H. pylori Infection in Young Dyspeptic Patients Necessitate Endoscopy?

BACKGROUND: Helicobacter pylori is an important gastrointestinal infective bacteria with many serious complications including gastric erosions and ulceration, duodenal ulcer, gastric carcinoma and MALT gastric lymphoma. The gastric biopsy is commonly performed in H. pylori-positive dyspeptic individuals, and many previous researchers studied the histopathological features of infected gastric biopsies however little previous studies focused on the histopathological findings in young population in comparison to the older one. AIM: To make a focus on the histopathological effects of H. pylori infection in young patients compared with the older one and predicts the need for endoscopy in this population, also to estimates the prevalence of infection in Iraqi patients. MATERIAL AND METHODS: the sample for this study is 180 patients in total, they attended Marjan medical city in Iraq for dyspepsia of more than 3 months and prepared for OGD. Patients asked for their permission to do immunological tests for H. pylori. Both serology for H. pylori antibodies and stool for antigen tests are used, and the case is included in the study only if both tests were positive, after OGD, the gastric biopsies are processed and examined histopathologically. RESULTS: Normal gastric biopsy is the most common histopathological finding in young (< 25 years) patients (75%) while chronic atrophic gastritis is the most common one in patients > 25 years age (57%). The prevalence of Helicobacter pylori infection in dyspeptic patients was 73.3%, the correlation between infection and sex was insignificant (p-value 0.06), and no significant correlation between infection and age (p-value 0.07) was concluded. CONCLUSION: H. pylori-related histopathological changes of gastric mucosa in young (< 25 years) are commonly mild and does not necessitate endoscopy at this age unless there are alarming signs.