Posts Categorized: New IEM



New Syndrome of GNB5 Deficiency

Posted by & filed under New IEM.

Lodder et al (AJHG 2016 Aug 10 [epub ahead of print] just reported a new genetic syndrome caused by defects in the gene GNB5. Clinical features of this condition include: developmental delay,  hypotonia, gastroesophageal reflux, retinal abnormalities, seizures and cardiac sinus-node dysfunction. Clinical expression of this disease is variable, and there appears to be some genotype-phenotype […]



New disorder of mitochondrial tRNA processing

Posted by & filed under New IEM, Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION.

Metodiev and colleagues (AJHG, 98(5), p993–1000, 5 May 2016 ) recently reported a new mitochondrial disorder of mt-tRNA processing. Pathogenic variants were found in in TRMT10C in  2 unrelated probands via whole exome sequencing protein. Clinical features of the probands included neonatal lactic acidosis, hypotonia, feeding difficulties, deafness, and early death from respiratory failure. TRMT10C encodes  mitochondrial RNase P […]



A syndrome of Golgi Dysfunction

Posted by & filed under New IEM.

I am quite used to thinking of only the mitochondria in terms of Mendelian Disorders of organelle dysfunction, which is my own bias because of the majority of the patients I see. However, I was very interested to read a recent article published by Schmidt et al (AJHG (2015)97, 855-861) in which they describe an […]



A new gene for Optic Neuropathy

Posted by & filed under New IEM.

Optic neuropathy with or without other features is a common cause of referral to mitochondrial specialists, and can pose a diagnostic challenge. Whereas isolated optic neuropathies in and of themselves are devastating enough, those associated with broader mitochondrial diseases can herald a multi-organ progressive disorder. Angebault et al (AJHG 2015 (97) 754-760) described a new […]



Mutations in SLC25A26 and mitochondrial methylation defects

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Kishita et al (AJHG 2015( 97) 761-768) just published a very interesting paper in which they describe that mutations in the mitochondrial S-adenosylmethionine (SAM) transporter SLC25A26 cause an autosomal recessive, severe mitochondrial disease. The mitochondrial functional defects are shown to be widespread and include RNA instability, translational defects, and cofactor biosynthetic defects. This leads one to wonder about […]



ECHS1 deficiency and mitochondrial disease

Posted by & filed under New IEM, Part 09: ORGANIC ACIDS.

Haack et al (Annals of Clinical and Translational Neurology, 2015, 2 (5) pp. 492-509) recently reported a disorder of encephalopathy, deafness, optic atrophy, and cardiomyopathy caused by mutations in short-chain enoyl-CoA hydratase  (ECHS1). This mitochondrial matrix enzyme functions in the oxidation of fatty acids and some amino acids (particularly valine). Patients present with a wide range […]



GTPBP3 abnormalities and mitochondrial disease

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GTPBP3 encodes for a modifier of a uridine located in the wobble position of several  mt-tRNA species. This base pair modification possibly has a role in the stabilization of tRNA-mRNA interactions. Recently, Kopajtich et al (Am J Hum Genet. 2014 Dec 4;95(6):708-20. doi: 10.1016/j.ajhg.2014.10.017) described 11 patients in 9 families with compound heterozygous or homozygous mutations […]



Cornelia de Lange Syndrome and HDAC8 mutations

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I recently saw a female patient with a clinically apparent genetic mosaic abnormality, including patchy distribution of hyperpigmentation, organ hemi-hypertrophy, and dental and skeletal abnormalities. Testing for obvious genetic causes including CDPX and Incontinentia Pigmenti were non-informative.  We sent whole exome sequencing which revealed a novel, presumed loss of function mutation in HDAC8. Loss-of-function mutations in HDAC8 were recently […]



Mutations in PTDSS1 cause Lenz-Majewski Syndrome

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Sousa et al. (Nature genetics, volume 46 (1) 2013: 70-76) recently reported that mutations in PTDSS1 cause Lenz-Majewski Syndrome (LMS). This discovery was made via whole exome sequencing on 4 affected patients. The mutations are gain of function mutations that impair negative feedback regulation of the end product, phosphatidylserine, Interestingly, while synthesis of phosphatidylserine is […]



A novel inborn error of coenzyme A biosynthesis implicated in neurodegeneration with brain iron accumulation (NBIA)

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Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. So far, the identified defects responsible for NBIA include: 1. pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in PANK2; 2. phospholipase A2-associated neurodegeneration (PLAN) due to mutations […]