De novo missense variants in exon 9 of SEPHS1 cause a neurodevelopmental condition with developmental delay, poor growth, hypotonia, and dysmorphic features.

Selenophosphate synthetase (SEPHS) plays an essential role in selenium metabolism. Two mammalian SEPHS paralogues, SEPHS1 and SEPHS2, share high sequence identity and structural homology with SEPHS. Here, we report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo. Structural modeling and biochemical assays were used to understand the effect of these variants on SEPHS1 function. We found that a variant at residue Trp352 results in local structural changes of the C-terminal region of SEPHS1 that decrease the overall thermal stability of the enzyme. In contrast, variants of a solvent-exposed residue Arg371 do not impact enzyme stability and folding but could modulate direct protein-protein interactions of SEPSH1 with cellular factors in promoting cell proliferation and development. In neuronal SH-SY5Y cells, we assessed the impact of SEPHS1 variants on cell proliferation and ROS production and investigated the mRNA expression levels of genes encoding stress-related selenoproteins. Our findings provided evidence that the identified SEPHS1 variants enhance cell proliferation by modulating ROS homeostasis. Our study supports the hypothesis that SEPHS1 plays a critical role during human development and provides a basis for further investigation into the molecular mechanisms employed by SEPHS1. Furthermore, our data suggest that variants in SEPHS1 are associated with a neurodevelopmental disorder.

Biotinidase deficiency: What have we learned in forty years?

BACKGROUND: Biotinidase deficiency (BD) is an autosomal recessively inherited disorder that was first described in 1982. Forty years after its first description, we compiled available clinical data on BD with the aim of generating a more comprehensive picture of this condition. METHODS: A systematic search strategy was performed in relevant databases without limits for publication date or languages. We screened 3966 records and included 144 articles reporting individuals with BD and their clinical presentation as well as the outcomes, when available. RESULTS: This study included 1113 individuals with BD. More than half (51.5%) of these individuals were diagnosed by newborn screening, 43.3% in presence of clinical symptoms and 5.2% due to family screening. We grouped symptomatic individuals into four main clinical presentations: neonatal-onset (<1 month; 7.9%), early childhood-onset (<2 years; 59.2%), juvenile-onset (2-16 years; 25.1%) and adult-onset (>16 years; 7.7%). BD affected five main organ systems: nervous system (67.2%), skin (53.7%), eye (34.4%), auditory (26.9%) and respiratory system (17.8%). Involvement was mainly multisystemic (82.2%) of individuals, whereas isolated system presentation was seen in only 17.2% of individuals. When reported, metabolic acidosis was present in 42.4% of symptomatic individuals and characteristic abnormal organic acid metabolites were found in 57.1%. Biotin treatment led to clinical stability or improvement in 89.2% of individuals. 1.6% of reported individuals with BD died due to non-availability of treatment or late diagnosis. CONCLUSION: Newborn screening has had a major positive impact on the outcome of many individuals with BD. However, undiagnosed and non-treated BD remains a health concern. Given the risk of mortality or complications associated with late or missed diagnosis if newborn screening is not available, a trial of biotin should be considered in undiagnosed infants and adults exhibiting suspected clinical signs. Enzymatic activity and/or analysis of genetic variants can readily confirm the diagnosis of BD.

Revisiting the administration of biotin to children with biotin-responsive disorders.

There continues to be questions and misconceptions about the administration of the vitamin, biotin, to children with the inherited biotin-responsive disorder, especially infants. Therefore, this commentary is intended to address the issues of biotin administration for healthcare workers, parents of children with the biotin-responsive disorders and the individuals with the disorders.

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.

Biotinidase deficiency is a rare, potentially treatable cause of peripheral neuropathy with or without optic neuropathy in adults.

BACKGROUND: We describe two adult brothers with lower limb neuropathy and one with progressive optic neuropathy. One brother was found to have profound biotinidase deficiency by identifying biallelic pathogenic variants of the BTD gene by whole exome sequencing, which was confirmed by markedly decreased serum biotinidase activity. CASE REPORT AND METHODS: The first brother had progressive optic atrophy and vision loss over 10 years and progressive peripheral neuropathy with weakness, pain, and fatigue for 20 years. Profound biotinidase deficiency was also identified in an older brother, who exhibited peripheral neuropathy since four years of age, but had no vision loss. RESULTS: The first brother's vision loss and neuropathy improved markedly with biotin in six months. However, the neuropathy of the other brother did not improve with 16 months of biotin therapy. CONCLUSIONS: The first brother's neurological issues partially reversed with biotin. However, the longer-term symptoms of the other brother were irreversible. These cases emphasize the importance of considering biotinidase deficiency in the differential diagnosis of adolescents and adults with peripheral neuropathy with or without optic neuropathy/atrophy before symptoms become irreversible. Although WES initially identified the disorder in this family, measuring serum biotinidase activity was a necessary confirmatory step after WES and is less expensive than performing whole exome sequencing.

Severe Distal Motor Involvement in a Non-compliant Adult With Biotinidase Deficiency: The Necessity of Life-Long Biotin Therapy.

Biotinidase deficiency is an autosomal recessive disorder in which affected individuals are unable to recycle biotin. Untreated, children usually exhibit hypotonia, seizures, ataxia, developmental delay, and/or hearing loss. Individuals diagnosed by newborn screening have an excellent prognosis with life-long biotin supplementation. We report a young adult diagnosed with profound biotinidase deficiency by newborn screening who was asymptomatic while on therapy. At 18 years of age, 6 months after voluntarily discontinuation of biotin, he developed a progressive distal muscle weakness. Molecular analysis of the BTD gene showed a pathogenic homozygous duplication c.1372_1373dupT p.(Cys458LeufsTer26) (1). Despite 16 months since reintroduction of biotin, muscle strength only partially recovered. Transition to adulthood in chronic metabolic diseases is known to be associated with an increased risk for non-compliance. Neurological findings in this adult are similar to those described in others with adult-onset biotinidase deficiency. Long-term prognosis in non-compliant symptomatic adult with biotinidase deficiency likely depends on the delay and/or severity of intervening symptoms until reintroduction of biotin.

Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder.

Hypusine is formed post-translationally from lysine and is found in a single cellular protein, eukaryotic translation initiation factor-5A (eIF5A), and its homolog eIF5A2. Biosynthesis of hypusine is a two-step reaction involving the enzymes deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). eIF5A is highly conserved throughout eukaryotic evolution and plays a role in mRNA translation, cellular proliferation, cellular differentiation, and inflammation. DHPS is also highly conserved and is essential for life, as Dhps-null mice are embryonic lethal. Using exome sequencing, we identified rare biallelic, recurrent, predicted likely pathogenic variants in DHPS segregating with disease in five affected individuals from four unrelated families. These individuals have similar neurodevelopmental features that include global developmental delay and seizures. Two of four affected females have short stature. All five affected individuals share a recurrent missense variant (c.518A>G [p.Asn173Ser]) in trans with a likely gene disrupting variant (c.1014+1G>A, c.912_917delTTACAT [p.Tyr305_Ile306del], or c.1A>G [p.Met1?]). cDNA studies demonstrated that the c.1014+1G>A variant causes aberrant splicing. Recombinant DHPS enzyme harboring either the p.Asn173Ser or p.Tyr305_Ile306del variant showed reduced (20%) or absent in vitro activity, respectively. We co-transfected constructs overexpressing HA-tagged DHPS (wild-type or mutant) and GFP-tagged eIF5A into HEK293T cells to determine the effect of these variants on hypusine biosynthesis and observed that the p.Tyr305_Ile306del and p.Asn173Ser variants resulted in reduced hypusination of eIF5A compared to wild-type DHPS enzyme. Our data suggest that rare biallelic variants in DHPS result in reduced enzyme activity that limits the hypusination of eIF5A and are associated with a neurodevelopmental disorder.

Biotinidase deficiency should be considered in individuals thought to have multiple sclerosis and related disorders.

BACKGROUND: Multiple sclerosis is a disorder of the central and peripheral nervous system of young and old adults that is characterized by muscle, coordination and vision abnormalities. Multiple sclerosis is likely due to numerous causes. METHODS: Recently, adolescents and adults with ophthalmological and or neurological findings have been diagnosed with biotinidase deficiency. These individuals have exhibited myelopathy, paresis and/or spastic diplegia/tetraplegia with or without optic neuropathy/vision loss. These older individuals with biotinidase deficiency were considered initially to have multiple sclerosis or similar disorders before they were determined to have biotinidase deficiency. RESULTS: If a symptomatic individual with biotinidase deficiency is treated with biotin early enough, the symptoms markedly improve or completely resolve, but if treatment is delayed, the symptoms may be irreversible. CONCLUSION: Therefore, although biotinidase deficiency is rare relative to that of multiple sclerosis, the disorder should be included in the differential diagnosis of individuals thought to have multiple sclerosis or related disorders. Biotinidase deficiency should be considered in individuals thought to have multiple sclerosis or related disorders.

ERRATUM: Laboratory diagnosis of biotinidase deficiency, 2017 update: a technical standard and guideline of the American College of Medical Genetics and Genomics.

This corrects the article DOI: 10.1038/gim.2017.84.

Laboratory diagnosis of biotinidase deficiency, 2017 update: a technical standard and guideline of the American College of Medical Genetics and Genomics.

Disclaimer: These ACMG Standards and Guidelines are intended as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these Standards and Guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of others that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinical laboratory geneticists should apply their professional judgment to the specific circumstances presented by the patient or specimen. Clinical laboratory scientists and geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Biotinidase deficiency is an autosomal recessively inherited disorder of biotin recycling that is associated with neurologic and cutaneous consequences if untreated. Fortunately, the clinical features of the disorder can be ameliorated or prevented by administering pharmacological doses of the vitamin biotin. Newborn screening and confirmatory diagnosis of biotinidase deficiency encompasses both enzymatic and molecular testing approaches. These guidelines were developed to define and standardize laboratory procedures for enzymatic biotinidase testing, to delineate situations for which follow-up molecular testing is warranted, and to characterize variables that can influence test performance and interpretation of results.

Corrigendum to "First contiguous gene deletion causing biotinidase deficiency: The enzyme deficiency in three Sri Lankan children" [Mol. Genet. Metab. Rep. 2 (2016) 81-84].

[This corrects the article DOI: 10.1016/j.ymgmr.2015.01.005.].

Developmental window of sensorineural deafness in biotinidase-deficient mice.

Biotinidase deficiency is an autosomal recessively inherited disorder that results in the inability to recycle the vitamin, biotin. If untreated, the disorder can result in a range of neurological and cutaneous symptoms, including sensorineural deficits and deafness. To understand early mechanistic abnormalities that may precede more generalized and nonspecific effects of metabolic deficits such as weight loss and acidosis, we have analyzed auditory brainstem responses (ABRs) in biotinidase-deficient knockout (Btd -/- ) mice in the periweaning period with or without dietary biotin supplementation. We find significant increases in the latency of wave V of the ABR elicited by pure tone stimuli at one octave intervals, which precede substantial increases in ABR thresholds. Finer interpeak latency analyses of these changes indicate they are confined to the latter ABR waves associated with the CNS and likely reflect slowed brainstem transmission time. In contrast, peripheral nervous system conduction velocity appears normal. Further, we find that biotin-supplementation after the onset of symptoms reverses the latency shifts, which has significant relevance for early treatment in patients. Finally, ABR latencies in Btd -/- mice fed a biotin-supplemented diet for the first month of life appear refractory to transmission time slowing during a subsequent bout of biotin deficiency. These data suggest a transient vulnerability window for biotin deficiency in the auditory brainstem. Finally, we also observe a developmental vulnerability window involving follicular melanosome production or melanocyte survival. Sensorineural deafness precedes peripheral hearing loss in developmental biotinidase deficiency and is transient if rescued by dietary biotin within a short developmental window.

Irreversibility of Symptoms with Biotin Therapy in an Adult with Profound Biotinidase Deficiency.

We report a 36-year-old woman who exhibited progressive optic atrophy at 13 years old, then stroke-like episodes and spastic diplegia in her 20s. Biotinidase deficiency was not readily considered in the differential diagnosis, and the definitive diagnosis was not made until pathological variants of the biotinidase gene (BTD) were found by exome sequencing. Profound biotinidase deficiency was confirmed by enzyme analysis. Unfortunately, her symptoms did not resolve or improve with biotin treatment. Biotin therapy is essential for all individuals with profound biotinidase deficiency and for preventing further damage in those who already exhibit irreversible neurological damage. Newborn screening for the disorder would have avoided years of clinical symptoms that now appear to be irreversible with biotin treatment.