Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood.

Four children in three unrelated families (one consanguineous) presented with lethargy, hyperlactatemia, and hyperammonemia of unexplained origin during the neonatal period and early childhood. We identified and validated three different CA5A alterations, including a homozygous missense mutation (c.697T>C) in two siblings, a homozygous splice site mutation (c.555G>A) leading to skipping of exon 4, and a homozygous 4 kb deletion of exon 6. The deleterious nature of the homozygous mutation c.697T>C (p.Ser233Pro) was demonstrated by reduced enzymatic activity and increased temperature sensitivity. Carbonic anhydrase VA (CA-VA) was absent in liver in the child with the homozygous exon 6 deletion. The metabolite profiles in the affected individuals fit CA-VA deficiency, showing evidence of impaired provision of bicarbonate to the four enzymes that participate in key pathways in intermediary metabolism: carbamoylphosphate synthetase 1 (urea cycle), pyruvate carboxylase (anaplerosis, gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched chain amino acids catabolism). In the three children who were administered carglumic acid, hyperammonemia resolved. CA-VA deficiency should therefore be added to urea cycle defects, organic acidurias, and pyruvate carboxylase deficiency as a treatable condition in the differential diagnosis of hyperammonemia in the neonate and young child.

Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans.

Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A.

Schinzel-Giedion syndrome: report of splenopancreatic fusion and proposed diagnostic criteria.

We report on the 46th patient with Schinzel-Giedion syndrome (SGS) and the first observation of splenopancreatic fusion in this syndrome. In the antenatal period, a male fetus was found to have bilateral hydronephrosis. Postnatally, in keeping with a diagnosis of SGS, there were large fontanelles, ocular hypertelorism, a wide, broad forehead, midface retraction, a short, upturned nose, macroglossia, and a short neck. Other anomalies included cardiac defects, widened and dense long bone cortices, cerebral ventriculomegaly, and abnormal fundi. Splenopancreatic fusion, usually encountered in trisomy 13, was found on autopsy. Schinzel-Giedion syndrome is likely a monogenic condition for which neither the heritability pattern nor pathogenesis has yet been determined. A clinical diagnosis may be made by identifying the facial phenotype, including prominent forehead, midface retraction, and short, upturned nose, plus one of either of the two other major distinguishing features: typical skeletal abnormalities or hydronephrosis. Typical skeletal anomalies include a sclerotic skull base, wide supraoccipital-exoccipital synchondrosis, increased cortical density or thickness, and broad ribs. Other highly supportive features include neuroepithelial tumors (found in 17%), hypertrichosis, and brain abnormalities. Severe developmental delay and poor survival are constant features in reported patients.

Sialic acid catabolism by N-acetylneuraminate pyruvate lyase is essential for muscle function.

Sialic acids are important components of glycoproteins and glycolipids essential for cellular communication, infection, and metastasis. The importance of sialic acid biosynthesis in human physiology is well illustrated by the severe metabolic disorders in this pathway. However, the biological role of sialic acid catabolism in humans remains unclear. Here, we present evidence that sialic acid catabolism is important for heart and skeletal muscle function and development in humans and zebrafish. In two siblings, presenting with sialuria, exercise intolerance/muscle wasting, and cardiac symptoms in the brother, compound heterozygous mutations [chr1:182775324C>T (c.187C>T; p.Arg63Cys) and chr1:182772897A>G (c.133A>G; p.Asn45Asp)] were found in the N-acetylneuraminate pyruvate lyase gene (NPL). In vitro, NPL activity and sialic acid catabolism were affected, with a cell-type-specific reduction of N-acetyl mannosamine (ManNAc). A knockdown of NPL in zebrafish resulted in severe skeletal myopathy and cardiac edema, mimicking the human phenotype. The phenotype was rescued by expression of wild-type human NPL but not by the p.Arg63Cys or p.Asn45Asp mutants. Importantly, the myopathy phenotype in zebrafish embryos was rescued by treatment with the catabolic products of NPL: N-acetyl glucosamine (GlcNAc) and ManNAc; the latter also rescuing the cardiac phenotype. In conclusion, we provide the first report to our knowledge of a human defect in sialic acid catabolism, which implicates an important role of the sialic acid catabolic pathway in mammalian muscle physiology, and suggests opportunities for monosaccharide replacement therapy in human patients.

Correlation of novel PAX6 gene abnormalities in aniridia and clinical presentation.

OBJECTIVE: To describe the clinical presentation and genotype of subjects with aniridia with a particular focus on foveal hypoplasia. DESIGN: Prospective cohort study. PARTICIPANTS: Thirty-three Canadian participants with aniridia and of various ethnic backgrounds residing in British Columbia. METHODS: Full ophthalmic examinations and posterior segment spectral domain-optical coherence tomography (SD-OCT) imaging were performed. Foveal hypoplasia was graded independently by 2 staff ophthalmologists. PAX6 sequencing was performed and chromosomal 11p anomalies investigated. Candidate gene and single-nucleotide polymorphism sequencing in genes functionally related to PAX6 were also studied. RESULTS: Best corrected visual acuities in the cohort ranged from 0.0 logMAR to no light perception. Total absence of iris tissue was seen in the majority (42 of 66 eyes). In those in whom SD-OCT was possible, foveal hypoplasia was seen in the majority (45 of 56 eyes, 80%). Molecular genetic defects involving PAX6 were identified in 30 participants (91%), including 4 novel PAX6 mutations (Gly18Val; Ser65ProfsX14; Met337ArgfsX18; Ser321CysfsX34) and 4 novel chromosome 11p deletions inclusive of PAX6 or a known PAX6 regulatory region. CONCLUSIONS: The number of PAX6 mutations associated with aniridia continues to increase. Variable foveal architecture despite nearly identical anterior segment disease in 4 participants with an Ex9 ELP4-Ex4 DCDC1 deletion suggested that molecular cues causing variation in disease in the posterior segment differ from those at play in the anterior segment. Results in 3 patients without identifiable PAX6 mutations and a review of the literature suggest that such cases be described as phenocopies rather than actual cases of the syndrome of aniridia.

Cost Analysis of Patients Referred for Inherited Heart Rhythm Disorder Evaluation.

BACKGROUND: Inherited heart rhythm disorders (IHRDs) are complex and uncommon arrhythmogenic conditions that can lead to sudden unexpected death in seemingly healthy individuals. Multidisciplinary programs can assist in the diagnostic testing of potentially affected individuals and their family members. METHODS: Patients evaluated in a specialized adult and pediatric IHRD clinic between April 2013 and February 2015 were characterized. The total costs per evaluation and diagnosis were calculated. Patients were divided according to referral indication (primary referral or family member). RESULTS: A total of 618 patients were evaluated (age 36 ± 21 years; 52% male), of which 274 (44%) were primary referrals and 344 (56%) were family members referred for cascade screening. Overall, 47% had at least 1 follow-up visit. Patients had a median of 3 tests; primary referrals required more tests (4 vs 2; P < 0.01). The median cost per patient was $1340 CAD. Evaluation of the primary referrals was costlier than family members ($3096 vs $983; P < 0.01). A definite or probable diagnosis was determined in 464 patients (77%), with no difference according to patient type (P = 0.18). The total cost per diagnosis was $4021 in primary referrals compared with $1277 in family members (P < 0.01). CONCLUSIONS: Clinical evaluation of patients with suspected IHRD results in a high diagnostic yield and costs aligned with other complex disorders involving multidisciplinary clinics. Evaluation costs are expectedly higher in primary referrals compared with targeted family screening.

Illness experience, depression, and anxiety in chronic fatigue syndrome.

OBJECTIVE: Given the high rate of psychiatric comorbidity with chronic fatigue syndrome (CFS), we considered two possible correlates of anxiety and depression: lack of illness legitimization and beliefs about limiting physical activity. METHOD: A total of 105 people diagnosed with CFS reported on their experiences with medical professionals and their beliefs about recovery and completed the depression and anxiety subscales of the Brief Symptom Inventory. RESULTS: Those who said that their physician did not legitimize their illness (36%) had higher depression and anxiety scores (P's<.05) than their counterparts. Those who believed that limiting their physical exertion was the path to recovery (55%) had lower depression and anxiety scores (P's<.01) than their counterparts. CONCLUSION: Lack of illness legitimization ranked high as a source of dissatisfaction for CFS patients, and it may aggravate psychiatric morbidity. Many CFS patients believed that staying within what they felt to be their physical limits would improve their condition. This belief, and possibly an accompanying sense of control over their symptoms, may alleviate psychiatric morbidity.

A characteristic syndrome associated with microduplication of 8q12, inclusive of CHD7.

This report describes a 4 year-old girl with history of hypotonia, developmental delay, and failure to thrive in infancy. She has cognitive impairment and multiple congenital anomalies, including Duane anomaly, Mondini malformation with associated deafness, external ear malformations, and atrial and ventricular septal defects. Array comparative genomic hybridization demonstrated a de novo tandem 6.9 Mb duplication of at least 15 genes in chromosome 8q12, inclusive of CHD7, with breakpoints at 58,388,614 bp and 65,306,097 bp (NCBI build 36.1). Loss of CHD7 by microdeletion or intragenic mutation causes CHARGE syndrome. There is one previous report of an individual with microduplication of 8q12 involving CHD7. He also had early hypotonia, cognitive impairment, Duane anomaly, sensorineural deafness and a congenital heart defect. This rather specific recurrent pattern of congenital anomalies associated with overlapping duplications of the genomic region containing CHD7 suggests that the phenotype in these two patients may be the result of abnormal CHD7 dosage.