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A deficiency of 3-hydroxyisobutyric acid dehydrogenase (HIBADH) has been recently identified as a cause of primary 3-hydroxyisobutyric aciduria in two siblings; the only previously recognized primary cause had been a deficiency of methylmalonic semialdehyde dehydrogenase, the enzyme that is immediately downstream of HIBADH in the valine catabolic pathway and is encoded by the ALDH6A1 gene. Here we report on three additional patients from two unrelated families who present with marked and persistent elevations of urine L-3-hydroxyisobutyric acid (L-3HIBA) and a range of clinical findings. Molecular genetic analyses revealed novel, homozygous variants in the HIBADH gene that are private within each family. Evidence for pathogenicity of the identified variants is presented, including enzymatic deficiency of HIBADH in patient fibroblasts. This report describes new variants in HIBADH as an underlying cause of primary 3-hydroxyisobutyric aciduria and expands the clinical spectrum of this recently identified inborn error of valine metabolism. Additionally, we describe a quantitative method for the measurement of D- and L-3HIBA in plasma and urine and present the results of a valine restriction therapy in one of the patients.

We report on a family in which four males over three generations are affected with X-linked recessive developmental delay, learning difficulties, severe behavioral difficulties and mild dysmorphic features. Plasma sterol analysis in three of the four affected males demonstrated increased concentrations of 8-dehydrocholesterol (8-DHC) and cholest-8(9)-enol. All four affected males had a novel hemizygous missense mutation, p.W47R (c.139T>C), in EBP. Functional studies showed raised levels of cholest-8(9)-enol in patient's cultured fibroblast cells, which were suppressed when the cells were incubated with simvastatin. EBP encodes 3β-hydroxysteroid-delta8, delta7-isomerase, a key enzyme involved in the cholesterol biosynthesis pathway. Mutations in EBP have previously been associated with Conradi–Hunermann–Happle syndrome (CHH), an X-linked dominant disorder characterized by skeletal dysplasia, skin, and ocular abnormalities, which is usually lethal in males. Four previous reports describe X-linked recessive multiple anomaly syndromes associated with non-mosaic EBP mutations in males, two at the same amino acid position, p.W47C. This phenotype has previously been described as “MEND” syndrome (male EBP disorder with neurological defects). The family reported herein represent either a novel phenotype, or an expansion of the MEND phenotype, characterized by extreme behavioral difficulties and a scarcity of structural anomalies. Simvastatin therapy is being evaluated in two males from this family. © 2014 Wiley Periodicals, Inc.

Desmosterolosis, a rare disorder of cholesterol biosynthesis, is caused by mutations in DHCR24, the gene encoding the enzyme 24-dehydrocholesterol reductase (DHCR24). To date, desmosterolosis has been described in only two patients. Here we report on a third patient with desmosterolosis who presented after delivery with relative macrocephaly, mild arthrogryposis, and dysmorphic facial features. Brain MRI revealed hydrocephalus, thickening of the tectum and massa intermedia, mildly effaced gyral pattern, underopercularization, and a thin corpus callosum. The diagnosis of desmosterolosis was established by detection of significant elevation of plasma desmosterol levels and reduced enzyme activity of DHCR24 upon expression of the patient’s DHCR24 cDNA in yeast. The patient was found to be a compound heterozygote for c.281G>A (p.R94H) and c.1438G->A (p.E480K) mutations. Structural and evolutionary analyses showed that residue R94 resides at the flavin adenine dinucleotide (FAD) binding site and is strictly conserved throughout evolution, while residue E480 is less conserved, but the charge shift substitution is accompanied by drastic changes in the local protein environment of that residue. We compare the phenotype of our patient with previously reported cases.