MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement.

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

Congenital duodenocolic fistula in a dog.

A one-year-old female cocker spaniel presented with a 6-month history of persistent diarrhoea. Abdominal ultrasonographic examination revealed mild diffuse thickening of the intestinal wall coupled with mesenteric lymphadenopathy. A connection between the duodenum and the colon was observed during an endoscopic procedure and confirmed by computed tomography. Surgical resection of the communication allowed remission of the diarrhoea. Histology showed a normal duodenal epithelium and muscular layer. A duodenocolic fistula is an abnormal connection within the digestive tract, which in humans is usually considered a complication of a local pathological condition. Due to the absence of a predisposing cause and, in view of the dog's age and histological results, a congenital origin was suspected.

Expanding the comprehensive national neonatal screening programme in the United Arab Emirates from 1995 to 2011.

The national neonatal screening programme in the United Arab Emirates currently includes 16 disorders: congenital hypothyroidism, sickle-cell diseases, congenital adrenal hyperplasia, biotinidase deficiency and 12 amino acid, organic acid and fatty acid disorders. This paper reports data since the programme started in January 1995 up to December 2011 on the incidence of screened disorders and the molecular basis of positive screened cases. Screening used a combination of tandem mass spectrometry, molecular technologies and biochemical analysis. A total of 750 365 infants were screened and 717 babies saved from associated morbidity and/or mortality. The incidence of screened disorders were 1:1 873 for congenital hypothyroidism, 1:14 544 for phenylketonuria, 1:3 526 for amino acid, organic acid and fatty acid disorders, 1:9 030 for classical congenital adrenal hyperplasia, 1:8 300 for biotinidase deficiency, 1:2 384 for sickle-cell disease and 1:121 for sickle-cell traits. Coverage of neonatal screening in the population reached 95% in 2010.

Expanding the comprehensive national neonatal screening programme in the United Arab Emirates from 1995 to 2011

The national neonatal screening programme in the United Arab Emirates currently includes 16 disorders: congenital hypothyroidism, sickle-cell diseases, congenital adrenal hyperplasia, biotinidase deficiency and 12 amino acid, organic acid and fatty acid disorders. This paper reports data since the programme started in January 1995 up to December 2011 on the incidence of screened disorders and the molecular basis of positive screened cases. Screening used a combination of tandem mass spectrometry, molecular technologies and biochemical analysis. A total of 750 365 infants were screened and 717 babies saved from associated morbidity and/or mortality. The incidence of screened disorders were 1:1 873 for congenital hypothyroidism, 1:14 544 for phenylketonuria, 1:3 526 for amino acid, organic acid and fatty acid disorders, 1:9 030 for classical congenital adrenal hyperplasia, 1:8 300 for biotinidase deficiency, 1:2 384 for sickle-cell disease and 1:121 for sickle-cell traits. Coverage of neonatal screening in the population reached 95% in 2010

The National Congenital Anomalies Register in the United Arab Emirates.

The National Congenital Anomalies Register is a population-based register covering all births in the United Arab Emirates. We evaluated the progress of the register and determined the prevalence of congenital anomalies (CAs) and associated maternal and neonatal risk factors. Total prevalence of CAs for 1999-2001 was 7.89/1000, 10.95/1000 and 7.92/1000 for live births, stillbirths and total births respectively. Rates were comparable to international rates for all districts except Dubai, Fujairah and Ras Al Khaimah. According to the International classification of diseases, the cardiovascular system was the most affected followed by CAs of chromosomal origin and the musculo-skeletal system. Birth defects were more common with older maternal age, grand multiparity, male babies, low-birth-weight babies and premature babies.

The National Congenital Anomalies Register in the United Arab Emirates

The National Congenital Anomalies Register is a population-based register covering all births in the United Arab Emirates. We evaluated the progress of the register and determined the prevalence of congenital anomalies [CAs] and associated maternal and neonatal risk factors. Total prevalence of CAs for 1999-2001 was 7.89/1000, 10.95/1000 and 7.92/1000 for live births, stillbirths and total births respectively. Rates were comparable to international rates for all districts except Dubai, Fujairah and Ras Al Khaimah. According to the International classification of diseases, the cardiovascular system was the most affected followed by CAs of chromosomal and the musculo-skeletal system. Birth defects were more common with older maternal age, gr and multiparity, male babies, low-birth-weight babies and premature babies

Prevalence of iodine deficiency disorders in the United Arab Emirates measured by raised TSH levels.

The United Arab Emirates National Screening Programme for Congenital Hypothyroidism was established in January 1998. The programme measures neonatal thyroid-stimulating hormone (TSH) levels of blood samples collected on filter paper on day 5 by heel prick. The prevalence of raised TSH levels (> 5 microU/mL whole blood) during 1998 and 1999 was used to evaluate the degree of iodine-deficiency disorders (IDD) in the population in different regions. The ratio of TSH profile in the present study and goitre rate in schools in a 1994 study were discrepant, although there was good correlation between the ratio of TSH profile and urinary iodine. The prevalence of raised TSH levels was < 3% in the Emirates overall, which is normal, and IDD varied from mild to normal problems in different regions.

United Arab Emirates National Newborn Screening Programme: an evaluation 1998-2000.

To evaluate the United Arab Emirate National Newborn Screening Programme we compared coverage, timeliness of programme indicators (age at sampling, recall and treatment initiation, timing of specimen delivery and laboratory results) and specimen quality with international standards. Recall rate, sensitivity, specificity, positive predictive values and relative incidence rates for phenylketonuria (PKU) and congenital hypothyroidism (CH) were calculated. Investigations for hypothyroidism included thyroid function studies (T3, T4, fT4 and TSH), technetium-99m thyroid scan when possible and thyroglobulin and thyroid antibodies when indicated. PKU investigations included plasma amino acids and measurement of biopterin defects. In the 6 years before December 2000, 138,718 neonates were screened. Relative incidences for CH and for classic PKU were 1:1570 and 1:20,050 respectively.

United Arab Emirates National Newborn Screening Programme: an evaluation 1998-2000

To evaluate the United Arab Emirate National Newborn Screening Programme we compared coverage, timeliness of programme indicators [age at sampling, recall and treatment initiation, timing of specimen delivery and laboratory results] and specimen quality with international st and ards. Recall rate, sensitivity, specificity, positive predictive values and relative incidence rates for phenylketonuria [PKU] and congenital hypothyroidism [CH] were calculated. Investigations for hypothyroidism included thyroid function studies [T3, T4, fT4 and TSH], technetium-99m thyroid scan when possible and thyroglobulin and thyroid antibodies when indicated. PKU investigations included plasma amino acids and measurement of biopterin defects. In the 6 years before December 2000, 138,718 neonates were screened. Relative incidences for CH and for classic PKU were 1:1570 and 1:20,050 respectively

Prevalence of iodine deficiency disorders in the United Arab Emirates measured by raised TSH levels

The United Arab Emirates National Screening Programme for Congenital Hypothyroidism was established in January 1998. The programme measures neonatal thyroid-stimulating hormone [TSH] levels of blood samples collected on filter paper on day 5 by heel prick. The prevalence of raised TSH levels [> 5 microU/mL whole blood] during 1998 and 1999 was used to evaluate the degree of iodine-deficiency disorders [IDD] in the population in different regions. The ratio of TSH profile in the present study and goitre rate in schools in a 1994 study were discrepant, although there was good correlation between the ratio of TSH profile and urinary iodine. The prevalence of raised TSH levels was < 3% in the Emirates overall, which is normal, and IDD varied from mild to normal problems in different regions