Mutations in known disease genes account for the majority of autosomal recessive retinal dystrophies.

Retinal dystrophies (RDs) are hereditary blinding eye conditions that are highly variable in their clinical presentation. The remarkable genetic heterogeneity that characterizes RD was a major challenge in establishing the molecular diagnosis in these patients until the recent advent of next-generation sequencing. It remains unclear, however, what percentage of autosomal recessive RD remain undiagnosed when all established RD genes are sequenced. We enrolled 75 families in which RD segregates in an apparently autosomal recessive manner. We show that the yield of a multigene panel that contains known RD genes is 67.5%. The higher yield (82.3%) when whole exome sequencing was implemented instead was often due to hits in genes that were not included in the original design of the panel. We also show the value of homozygosity mapping even during the era of exome sequencing in uncovering cryptic mutations. In total, we describe 45 unique likely deleterious variants (of which 18 are novel including one deep intronic and one genomic deletion mutation). Our study suggests that the genetic heterogeneity of autosomal recessive RD is approaching saturation and that any new RD genes will probably account for only a minor role in the mutation burden.

Differences in physician compliance with guideline on lipid profile determination within 24 h after acute myocardial infarction.

OBJECTIVE: To evaluate the American College of Cardiology/American Heart Association guidelines on blood lipid testing within 24 h of the onset of chest pain in patients with myocardial infarction. SUBJECTS AND METHODS: This is a cross-sectional observational study on 83 patients (77 male, 6 female) admitted into the Coronary Care Units of the Al-Amiri and Mubarak Al-Kabeer Hospitals, Kuwait with myocardial infarction. The lipid profiles were obtained within 24 h of the onset of chest pain. Twenty patients were on treatment with statins prior to admission. Diagnosis of myocardial infarction in all patients was based on standard criteria. Total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and triglycerides (Tg) were measured and low-density lipoprotein (LDL) cholesterol was calculated. RESULTS: Twenty-three patients had normal cardiac markers on admission but later developed increased serum markers and ECG changes of acute myocardial infarction. Mean (95% confidence interval) TC, HDL, Tg and LDL were 5.1 (4.8-5.4); 0.93 (0.88-0.98); 1.85 (1.56-2.14), and 3.39 (3.13-3.65) mmol/l, respectively. 70% of the patients had normal or only mild elevations of LDL with low HDL and poor HDL:TC ratio (<20%). Thirty-eight patients had low HDL (<0.9 mmol/l) and only 22 (27%) patients met the National Cholesterol Education Program guideline of target LDL <2.6 mmol/l. Fifty-six patients were classified as having the metabolic syndrome according to the criteria of the WHO. CONCLUSION: The findings indicate that HDL appears to be the main lipid risk factor in patients presenting with AMI in Kuwait, therefore primary prevention strategies should focus on treatment modalities that increase HDL. We recommend that the lipid profile should be done within 24 h of admission and lipid-lowering therapy initiated as part of secondary prevention strategy.

Carnitine palmityl transferase I deficiency.

Carnitine palmityl transferase I is the key enzyme in the carnitine dependent transport of long chain fatty acids across the mitochondrial inner membrane and its deficiency results in a decrease rate of fatty acids beta-oxidation with decreased energy production. We reported a family of 3 affected siblings who are the product of a first degree cousin marriage. The first 2 presented with typical Reye-like syndrome with unconsciousness, hepatomegaly, hypoglycemia, hyperammonemia and very high liver enzymes. Liver biopsy showed steatosis. On screening of the complete family, the 3rd sibling was found to have hepatomegaly. The 3 siblings showed an acyl carnitine profile with very high free carnitine with almost absent long chain acyl carnitines, suggestive of carnitine palmityl transferase I deficiency. This was confirmed by enzyme analyses in fibroblast cultures. These patients were effectively treated with a diet high in carbohydrate, low in long chain fatty acids with medium chain triglycerides. In conclusion, carnitine palmityl transferase I deficiency is an important cause of Reye-like syndrome, which may be treated easily with very good results if detected early in life.

Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family.

The autosomal recessive multicentric osteolytic disorders of childhood-Torg, Winchester, and François syndromes-predominantly affect the carpal, tarsal, and interphalangeal joints, and their progressive bone loss and crippling arthritic deformities mimic severe juvenile rheumatoid arthritis. In a consanguineous Saudi Arabian family two affected sibs with facial anomalies and short stature displayed a distal arthropathy of the metacarpal, metatarsal, and interphalangeal joints starting in the first few months of life that eventually progressed to the proximal joints and resulted in crippling ankylosis and severe generalized osteopenia. Facial changes included proptosis, a narrow nasal bridge, bulbous nose, and micrognathia. In addition, they had large, painful fibrocollagenous palmar and plantar pads and mild body hirsutism. Affected individuals were of normal intelligence and had normal renal function. Routine hematologic, chemistry, and rheumatoid studies were within normal limits. Histologic examination of bone marrow and an interphalangeal joint biopsy were not informative. The autosomal recessive inheritance, clinical, and radiologic characteristics of the affected sibs suggested that they had a form of multicentric osteolysis most closely resembling the Torg syndrome, but with a unique facial appearance, fibrocollagenous pads, and body hirsutism not noted in the original description of the syndrome.

Malonic aciduria.

Three infants with malonic aciduria are reported, one of whom could be studied in detail. All children had severe and progressive encephalopathy with intermittent ketoacidosis and hypoglycemia. One infant died of cardiomyopathy. Biochemical studies revealed that one patient had neither malonyl-CoA decarboxylase nor glutaryl-CoA dehydrogenase deficiencies. This variant of malonic aciduria is different from that of four patients previously reported, both in its clinical and biochemical presentations. The biochemical pathology of this variant malonic aciduria is unknown.

Experience of King Faisal Specialist Hospital and Research Center with Saudi organic acid disorders.

The Inborn Errors of Metabolism and Neurology Services of the King Faisal Specialist Hospital and Research Centre (KFSH&RC) and Armed Forces Hospital have received more than 1,500 patients suspected of having an organic acid disorder (OAD) during a period of four years. Of these, 307 patients suspected of having an organic acid disorder (OAD) during a period of four years. Of these, 307 patients, approximately 20%, had a clearly identifiable disorder. Identified OAD's constituted one-quarter of all patients diagnosed as having various types of inborn errors of metabolism during this period, in these clinical services. Prolonged follow-up was available in the majority of cases, allowing detailed clinical, neuroradiologic and neurophysiologic descriptions. Fifty patients (16%) had rare disorders by standards in the West. Approximately 25% were 'neurologic organic acidurias.' This is a new term we are introducing for OAD's manifesting primarily with neurologic signs, but without appreciable acidosis, hypoglycemia or hyperammonemia. In this special issue, we present the KFSH&RC experience with the rare disorders as individual articles. We estimate the frequency of OAD's in Saudi Arabia as 1/740 births. The increased frequency of OAD's in Saudi Arabia is probably due to increased consanguinity, since most OAD's occurred in excess in certain tribes; and due to increased surveillance and testing by our group. Saudi Arabia provides a unique opportunity for research in this area of pediatrics.

3-Methylglutaconic aciduria: ten new cases with a possible new phenotype.

3-Methylglutaconic aciduria is an organic aciduria with diverse phenotypic presentations. In more than half of the cases it is a 'neurologic or silent organic aciduria', and, except for one subtype, the biochemical defect is unknown. This report describes 10 new patients. Four of them presented with early global neurologic involvement and arrested development. They rapidly became demented, developed myoclonus or tonic-clonic seizures, spastic quadriplegia, deafness and blindness, and died. Three had acidosis and hypoglycemia neonatally; later, myoclonus and deafness, and eventually severe mental retardation and spastic quadriplegia developed. One patient died. In three children who presented with sudden onset of extrapyramidal tract symptoms, with or without optic atrophy, the clinical presentation was significantly different from that described either for 'unspecified' type or for Costeff syndrome. All three patients showed clinical improvement soon after treatment with coenzyme Q.

A new patient with alpha-ketoglutaric aciduria and progressive extrapyramidal tract disease.

A 4.5-year-old boy with chronic progressive encephalopathy is described. The clinical presentation initially included seizures and hypotonia which later evolved into severe extrapyramidal disease and dementia. The gas chromatography/mass spectrometry (GC/MS) analysis of urine indicated that alpha-ketoglutarate was increased 210 times and aconitic acid 80 times. No disturbance of acid/base balance, lactic acid or ammonia metabolism accompanied this clinical picture. The fibroblasts contained 29% of normal alpha-ketoglutarate dehydrogenase activity, while the activity of another mitochondrial marker enzyme, glutamate dehydrogenase, was normal. The neuroimaging studies revealed bilateral striatal necrosis. The clinical and biochemical findings were almost identical to two previously reported patients. Experience with this patient emphasizes the need for detailed organic acid biochemical investigation in any progressive encephalopathy and that extrapyramidal tract signs should evoke the possibility of alpha-ketoglutaric aciduria, among other 'neurologic organic acidemias'.

Unusual presentations of propionic acidemia.

The files of 25 patients with propionic acidemia (PA), followed by the Inborn Errors of Metabolism Service (IEMS) at King Faisal Specialist Hospital and Research Centre (KFSH & RC) from 1990 to 1993, were studied retrospectively. In 14 patients PA presented acutely with acidosis, hyperammonemia and thrombocytopenia, while in 11 patients the presentation of the disease was unusual. In the latter group, two neonates with PA initially appeared as a primarily hyperammonemic metabolic disease. In two other neonates the vomiting was so severe that they were diagnosed as intestinal obstruction in referral hospitals. The presentation in three infants was primarily as an immune disorder. In four infants, PA appeared as an acute or chronic encephalopathy, i.e. as a silent organic acidemia, with few other findings of the disease. The clinical picture of PA includes facial and nipple dysmorphia, severe hypotonia and vomiting. Severe thrombocytopenia is the hallmark of the metabolic crisis. In one patient it was noticed late and caused intracranial hemorrhage, while in three others intracranial bleeding caused death. The prognosis in PA remained grave despite rigorous treatment. Only seven of the 25 PA patients remained to have a normal life-style, while eight patients expired. The diagnosis is readily achieved by urine gas chromatography/mass spectrometry (GC/MS), by tandem mass spectrometry (MS/MS), or by enzyme analysis of fibroblasts. While there may be both examiner- and patient-related reasons for the variations in the presentation of PA, one other reason may be the heterogeneity of the molecular defect in propionyl-CoA carboxylase.

The combined use of intravenous and oral calcium for the treatment of vitamin D dependent rickets type II (VDDRII).

OBJECTIVE: Some patients with rickets are resistant to vitamin D and its analogues; we therefore assessed whether or not normal mineralization could be achieved in the absence of an intact 1,25(OH)2D3 receptor-effector system, by the use of intravenous high dose calcium infusion, followed by high dose oral calcium. DESIGN: We studied two patients with vitamin D dependent rickets type II and with absent responses to either high dose calcitriol or to oral calcium alone. Daily infusions equivalent to up to 1.4 g elemental calcium supplemented with oral phosphate were given for a period of 3.5 months for the elder sister and 2 months in the younger brother. Both patients were then treated by weekly calcium infusions for 5 months, followed by maintenance on oral calcium equivalent to up to 6 g elemental calcium per day. PATIENTS: Two siblings of consanguineous parents, a girl aged 28 months and a boy aged 10 months with vitamin D dependent rickets type II. MEASUREMENTS: Measurements of serum and urine calcium, phosphate and serum alkaline phosphatase were obtained before, during and after the calcium infusions. Twenty-four-hour urinary minerals, electrolytes, creatinine clearance, serum PTH and vitamin D metabolites were measured prior to calcium infusion, then repeated at 2-monthly intervals. Glomerular filtration rate, kidney ultrasound and CT scan were done at 6-monthly intervals. A scalp biopsy was done at the end of i.v. calcium treatment. RESULTS: The daily infusions of calcium supplemented with oral phosphate resulted in biochemical responses with normalization of calcium and phosphate in 3-5 days, and of alkaline phosphatase and PTH in 1.5-2 months. Radiological evidence of healing was seen in 42 days. A total of 3.5 months of daily calcium infusion in the elder sister and 2 months in the younger brother resulted in complete healing biochemically and radiologically, with improvement in height. The patients are under current follow-up, with no evidence of nephrocalcinosis or deterioration of glomerular filtration rate. CONCLUSIONS: (a) The use of intravenous high dose calcium infusions followed by high dose oral calcium is an effective method of treatment of vitamin D dependent rickets type II. (b) The treatment was more effective since it was started early in the course of the disease and led to early healing and better growth with prevention of bone deformities. (c) Early treatment may also lead to improvement in alopecia, the mechanism for which needs to be elucidated. ABBREVIATIONS: 1,25(OH)2D3, 1,25-dihydroxyvitamin D3 (calcitriol); 24-OHase, 25-(OH)D(3),24-hydroxylase; 1 alpha-(OH)D3, 1 alpha-hydroxyvitamin D3; 25(OH)D3, 25-hydroxyvitamin D3; 1 alpha-OHase, 1 alpha-hydroxylase; PTH, parathyroid hormone.

Vitamin D-dependency rickets type II: truncated vitamin D receptor in three kindreds.

Fibroblasts from three patients with vitamin D-dependency rickets type II were used to study mutations in the 1,25-dihydroxyvitamin D3 receptor responsible for this hereditary disease. Normal human fibroblasts contain 43 +/- 13 fmol receptor/mg protein as determined by immunoradiometric assay and 22 +/- 3 fmol/mg by ligand binding assay. The fibroblasts from the rachitic patients contained no receptor detectable by either method. The 1,25-(OH)2D receptor cDNA for cells from each kindred was produced from total RNA using reverse transcription and polymerase chain reaction amplification. When these cDNAs were sequenced, it was found that each cell line contained a nucleotide substitution resulting in a stop codon in the coding sequence. The predicted resultant receptor protein is 69 amino acids long in one family, and 148 and 291 amino acids long in two other families. These truncated proteins have little or no 1,25-dihydroxyvitamin D3-binding domain accounting for 1,25-dihydroxyvitamin D resistance.

Saudi variant of multiple sulfatase deficiency.

We describe eight patients with multiple sulfatase deficiency (MSD, or Austin's disease) who differ phenotypically from classic neonatal-, childhood-, or juvenile-onset MSD. The age of onset was in childhood. The patients presented with somatic and facial features of mucopolysaccharidosis reminiscent of Maroteaux-Lamy and Morquio syndromes. They differed from classic MSD by the presence of corneal cloudiness, macrocephaly, severe dysostosis multiplex, and gibbus and the absence of ichthyosis, retinal degeneration, severe deafness, severe mental retardation, and dementia. The main neurologic presentation was cervical cord compression due to axis abnormalities. Despite neuroradiologic evidence of white-matter changes, neurologic presentation was not like metachromatic leukodystrophy. The sulfatase deficiencies were more marked than in the classic juvenile form of MSD, but less marked than in the classic childhood-onset form of MSD. Steroid sulfatase activity was spared except in one patient. This Saudi variant of MSD accounts for 5% of all lysosomal storage diseases in the Cell Repository Registry of our Inborn Errors of Metabolism Laboratory.

Response of 6-pyruvoyl-tetrahydropterin synthase deficiency to tetrahydrobiopterin.

We have given tetrahydrobiopterin (BH4) in doses ranging from 2.5 to 20 mg/kg/day, each for a duration of 5 days to three patients with 6-pyruvoyltetrahydropterin synthase deficiency. As small a dose as 2.5 mg/kg/day BH4 reduced the blood phenylalanine to normal levels. However, the required dose of BH4 to reduce neopterin and to increase urine biopterin was 5 to 10 mg/kg/day, while 20 mg/kg/day was required for biopterin to appear in cerebrospinal fluid. The results suggest that BH4 effectively reduces endogenous neopterin synthesis. The dose of BH4 needed to normalize liver phenylalanine hydroxylase is one eighth to one fourth that required for normal neurotransmitter metabolism in the central nervous system.

Biopterin-dependent hyperphenylalaninemia due to deficiency of 6-pyruvoyl tetrahydropterin synthase.

We describe the clinical, neurologic, and biochemical findings in 10 patients with 6-pyruvoyl tetrahydropterin synthase (6-PTS) deficiency from seven families, all of whom originate from one large tribe in Saudi Arabia. This deficiency presents with severe, early onset of failure to thrive, neurologic deterioration, and morbidity and mortality secondary to repeated episodes of bronchopneumonia or cardiorespiratory abnormalities. The urinary pterin excretion pattern indicates deficient activity of 6-PTS, which has been confirmed by direct enzyme assay in red blood cells of three patients. We treated our patients with combined use of tetrahydrobiopterin 20 mg/kg/d, L-dihydroxyphenylalanine 15 mg/kg/d, carbidopa 3.75 mg/kg/d, and L-5-hydroxytryptophan 5 mg/kg/d. Neurologic findings improved significantly in all after 5 to 24 months. Although head circumference and weight returned to the lower limit of normal in four, height normalized only in one of seven patients. Despite an unrestricted diet during combined therapy, blood phenylalanine and urinary excretion of neopterin and biopterin returned to normal.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency in Saudi Arabia.

Deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase has been studied in 11 Saudi infants. The diagnosis was established by the measurement of enzyme activity in lymphocytes, in fibroblasts and, in seven patients, by the gas chromatography/mass spectrometer pattern of excreted organic acids in the urine. In seven infants the disease caused a devastating acidotic attack within the first day of life, while in two the crisis occurred by the third day of life. In two infants from one family the disease appeared later in infancy. The clinical presentation of an acidotic attack is lethargy, hyperpnoea, tachypnoea and seizures, either at birth (two infants), following first feeding (in five infants), or following vomiting or refusal of food in later infancy. The acidotic attacks recurred later in life following minor illness or refusal to eat. The acidosis of this enzyme deficiency progresses rapidly, leading to cardiopulmonary arrest and death within hours of onset unless treated promptly. In four surviving infants diagnosed and treated early, development is normal. Magnetic resonance and computerized tomography brain scans in these infants, however, show white matter lesions and mild atrophy.

Prevalence of different types of lysosomal storage diseases in Saudi Arabia.

The frequency of different types of lysosomal storage diseases in 125 referred cases, collected over three years, was compared to the occurrence elsewhere. The data suggest that mucopolysaccharidosis (MPS) type IVA (Morquio disease), multiple sulphatase deficiency, Niemann-Pick disease type B, GM2 gangliosidosis type '0' (Sandhoff disease), and ceroid lipofuscinosis (Jansky-Bielschowsky and Batten-Spielmeyer-Vogt syndromes) are encountered frequently in Saudi Arabia, as compared to other storage diseases. In contrast, some other diseases such as the adult variant of Gaucher's disease were not observed. Half of the GM2 gangliosidosis type '0' cases originated from one large tribe in the country. Other conditions did not show tribal predilection. The ceroid lipofuscinosis cases in Saudi Arabia originated from four large families. Consanguineous marriages taking place within tribal boundaries probably account for the pattern observed.