A Mild Skeletal Dysplasia Caused by a Biallelic Missense Variant in the SLC35D1 Gene.

Introduction: Biallelic variants in the SCL35D1 gene have been originally associated with a severe skeletal dysplasia called "Schneckenbecken dysplasia" because of the resemblance of the pelvic shape to a snail. More recently, SLC35D1 variants have been associated with much milder phenotypes of skeletal dysplasia. Our report describes one such individual with a novel SLC35D1 variant. Case Presentation: A 17-year-old male with a coarse face and short stature was referred to our clinic. On his radiographic imaging, shortness of the long bones and metaphyseal flaring were detected. Using a clinical exome panel, we discovered a novel homozygous missense variant in the SLC35D1 gene, c.899G>T (p.Gly300Val). Conclusions: We identified a biallelic variant that was causative for a mild skeletal dysplasia and showed its phenotypic effects. Our observation confirms the existence of nonlethal skeletal dysplasias associated with biallelic SLC35D1 variants and suggests the existence of a phenotypic spectrum.

Mitochondrial trifunctional protein deficiency as a polyneuropathy etiology in childhood.

BACKGROUND: The mitochondrial trifunctional protein (MTP) is a multienzyme complex of the fatty acid betaoxidation cycle. Mitochondrial trifunctional protein deficiency (MTPD), a rare condition that leads to failure of converting certain fats to energy is characterized by decreased activity of three enzymes in the enzyme complex. Signs and symptoms of MTPD may present during infancy or later in life; those that begin after infancy include hypotonia, muscle pain, rhabdomyolysis, and peripheral neuropathy. We report a Turkish boy diagnosed with MTPD after being investigated for polyneuropathy of unknown origin since infancy. CASE: A 5.5-year-old male patient was admitted to our clinic with complaints of weakness in the arms and legs, physical inactivity compared to his peers, fatigue, weakness and, difficulty in climbing stairs since infancy. Electroneuromyography (ENMG) analysis showed moderate symmetric distal sensorimotor and axonal neuropathy. On the background of chronic polyneuropathy, the patient had acute relapsing episodes with progressively worsening severity in the follow-up period until 12.5 years of age. Whole exome sequencing (WES) was performed in the patient and, revealed that the patient had a homozygous c.1390G > A (p.Gly464Ser) pathogenic variant of the HADHB gene. Although rhabdomyolysis is a well defined accompanying clinical feature of MTPD, it was not present in our patient who only had worsening muscle weakness during attacks. CONCLUSION: On the background of chronic polyneuropathy and acute relapsing episodes triggered by fasting or illnesses and rhabdomyolysis physicians should suspect disorders of the fatty acid beta-oxidation cycle.

Frequency and status of depression and anxiety in mothers of children with inborn errors of metabolism with restricted diet, with and without risk of metabolic crises.

OBJECTIVES: This study aimed to investigate the frequency and status of depression and anxiety among mothers of children with inborn errors of metabolism (IEM) who were on a restricted diet and previously experienced metabolic crises. METHODS: This cross-sectional multicenter descriptive study included 93 children with IEM who were on restricted diet. The patients were divided into two groups: those who had experienced metabolic crises (n=44, urea cycle defect, organic acidemia, maple syrup urine disease, hereditary fructose intolerance) and those who had not experienced previous metabolic crises (n=49; phenylketonuria, galactosemia, and non-ketotic hyperglycinemia). The control group comprised 37 healthy children. The mothers of the patients and control participants answered a questionnaire about their and their children's demographic and clinical characteristics and completed the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI-S and STAI-T). RESULTS: The maternal BDI, STAI-S, and STAI-T scores were 6.3±5.2, 36.1±11.2, and 39.9±8.8, respectively, in the control group. The maternal BDI, STAI-S, and STAI-T scores of the children who had experienced (19.2±9.7; 44.0±12.4; 47.9±10.6) and those who had not experienced (13.9±9.1; 40.7 ±8.6; 45.3±8.3) a crisis were significantly higher than for the controls. The BDI score was significantly higher for the mothers of children who had experienced a crisis (p=0.011), whereas no significant difference was determined between the two patient groups regarding STAI-S and STAI-T scores. The mothers of four children who had experienced metabolic crises were on antidepressant therapy. CONCLUSION: Although their children were on a similar restricted diet, the mothers of children who previously experienced or who had the risk of experiencing metabolic crises had higher depression scores as compared with the mothers of children who did not experience a previous crisis. Early supportive therapy may be required for the families of these patients to lower the burden of stress.

Alkaptonuria in Turkey: Clinical and molecular characteristics of 66 patients.

Alkaptonuria (AKU) is an inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase (HGD) as a result of a defect in the HGD gene. HGD enzyme deficiency results in accumulation of homogentisic acid (HGA) in the body, which in turn leads to multisystemic clinical symptoms. The present study aimed to investigate the presenting symptoms, age at diagnosis, and clinical and genetic characteristics of AKU patients followed-up in different centers in Turkey. In this cross-sectional, multicenter, descriptive study, medical records of 66 AKU patients were retrospectively evaluated. Patients' data regarding demographic, clinical and genetic characteristics were recorded. HGD database (http://hgddatabase.cvtisr.sk/) was used to identify HGD gene variants. Of the patients, 37 (56.1%) presented with isolated dark urine and 29 (43.9%) were diagnosed based on the clinical symptoms or family screening. One of these patients was on follow-up for 2 years due to Parkinsonism and was diagnosed with AKU on further analyses. Signs of ochronosis such as joint pain, low back pain and renal stones developed in childhood in 7 patients. Eight patients were diagnosed with depression via psychiatric evaluation. There were 14 (21.2%) patients operated on for ochronosis. The most frequent mutation observed in the patients was c.175delA, which was followed by c.674G > A and c.1007-2A > T mutations. Four novel mutations (c.189G > A, c.549+1G > T, c.1188+1G > A, and c.334 T > G) were identified in the patients included in the study. In addition to the known signs such as dark urine and skin pigmentation, symptoms involving different systems such as neurological findings and depression can also be encountered in AKU patients. The presence of a change in urine color needs to be questioned in patients presenting with different symptoms such as arthralgia/arthritis, renal stones or low-back pain, particularly in childhood, when skin ochronosis is not pronounced, and further examination should be performed.