George van der Watt

Glutaric aciduria type 1 in South Africa-high incidence of glutaryl-CoA dehydrogenase deficiency in black South Africans.

Glutaric Aciduria type 1 (GA 1) is an inherited disorder of lysine and tryptophan catabolism that typically manifests in infants with acute cerebral injury associated with intercurrent illness. We investigated the clinical, biochemical and molecular features in 14 known GA 1 patients in South Africa, most of whom were recently confirmed following the implementation of sensitive urine organic acid screening at our laboratory. Age at diagnosis ranged from 3days to 5years and poor clinical outcome reflected the delay in diagnosis in all but one patient. Twelve patients were unrelated black South Africans of whom all those tested (n=11) were found homozygous for the same A293T mutation in the glutaryl-CoA dehydrogenase (GCDH) gene. Excretion of 3-hydroxyglutarate (3-OHGA) was >30.1μmol/mmol creatinine (reference range <2.5) in all cases but glutarate excretion varied with 5 patients considered low excretors (glutarate <50μmol/mmol creatinine). Fibroblast GCDH activity was very low or absent in all of five cases tested. Heterozygosity for the A293T mutation was found 1 in 36 (95% CI; 1/54 - 1/24) unrelated black South African newborns (n=750) giving a predicted prevalence rate for GA 1 of 1 in 5184 (95% CI; 1/11664 - 1/2304) in this population. GA 1 is a treatable but often missed inherited disorder with a previously unrecognised high carrier frequency of a single mutation in the South African black population.

Euthyroid Patient with Elevated Serum Free Thyroxine

A 32-year-old female patient presented complaining of increased flushing, perspiration and heat intolerance of 3 months’ duration. Medical history included idiopathic thrombocytopenic purpura of 4 years’ duration, which had been treated by splenectomy after failed immunosuppression with prednisone and azathioprine and was currently in remission. On examination, she was found to be clinically euthyroid without a goiter. She had also developed a diffuse erythematous papular rash on the face and back, with bullous lesions on the chest. Immunofluorescent antibody studies performed on a punch biopsy of skin were positive for several autoantibodies, leading to a diagnosis of subacute cutaneous lupus erythematosus. This diagnosis was further characterized by positive titers of nuclear and double-stranded DNA autoantibodies in the serum. Thyroid function testing on an Advia Centaur® Immunoassay System (Siemens Medical Solutions Diagnostics) revealed an increased concentration of serum free thyroxine (FT4)1 of 90.1 pmol/L (6.97 ng/dL) (reference range 11.5–22.7 pmol/L), a nonsuppressed thyroid-stimulating hormone (TSH) concentration of 1.8 mIU/L (1.8 μIU/mL) (reference range 0.35–5.5 mIU/L), and normal free triiodothyronine (FT3) concentration of 4.2 pmol/L (0.33 ng/dL) (reference range 3.5–6.5 pmol/L). Repeat investigation 1 and 2 months later revealed a progressive increase in FT4 to 125.3 pmol/L (9.7 ng/dL) and ≥155 pmol/L (≥12.0 ng/dL), respectively. TSH and FT3 remained within reference intervals, as did total T4 by RIA, at 155 nmol/L (12 μg/dL) (reference range 58–161 nmol/L). Furthermore, she tested positive for antithyroperoxidase antibodies at 110 IU/L (reference range <37 IU/L) and antithyroglobulin antibodies at 149 IU/L (reference range <98.1 IU/L). An investigation of her disconcordant thyroid function tests was initiated. Increased serum FT4 concentrations, with a nonsuppressed TSH, are most often seen with erratic thyroxine replacement therapy. Other less common causes include antibody interference in the FT4 assay causing falsely increased …

Whole blood mitochondrial DNA depletion in South African HIV-infected children

Nucleoside reverse transcriptase inhibitors (NRTIs) affect mitochondrial DNA polymerase gamma causing significant toxic effects, including fatal lactic acidosis. Little is known about mitochondrial DNA (mtDNA) in human immunodeficiency virus (HIV) infected children who face a lifetime exposure to these agents. We performed a cross sectional observation of mtDNA levels in whole blood in a pediatric population to ascertain the relationship between mtDNA, NRTI regimens and parameters of HIV-infection severity. Whole blood mitochondrial / nuclear DNA (mt:nDNA) ratios were determined by real-time PCR in three groups: 27 presumed HIV-negative, 89 HIV-infected, NRTI-treated and 62 HIV-infected treatment-naive children. Multivariate analysis was used to identify variables independently associated with mtDNA depletion. Mean mt:nDNA ratios were lower (p

Teenaged Siblings with Progressive Neurocognitive Disease

Two siblings were referred for workup for progressive neurological deterioration. The elder sibling was a 16- year-old boy who had been asymptomatic until 9 years of age when he developed walking difficulty that progressed to a bed-bound state followed by regression of cognitive function and generalized tonic clonic seizures. The younger sibling was a 14-year-old girl with onset of similar symptoms at the age of 6 years. The siblings were the eldest of 6 children from a family with no history of consanguinity. Both children principally ate a high-carbohydrate (maize)-based diet with sporadic access to fresh produce and animal protein. They had reached normal developmental milestones until the onset of symptoms. Both children had been treated unsuccessfully with sodium valproate. On examination, they demonstrated minimal communication skills and severe cognitive impairment. They had spastic paralysis of all extremities. Electroencephalography in the elder sibling revealed generalized, highly potentially epileptogenic foci, and a brain computed tomography scan demonstrated marked cerebral atrophy with minimal white matter. Initial laboratory investigations, including a complete blood count, measurement of electrolytes and urea, and thyroid and liver function tests, were all within reference intervals. Syphilis serology was negative. Screening for inherited metabolic diseases included measurements of plasma amino acids and urine organic acids. Selected laboratory results of the elder boy are provided in Table 1. View this table: Table 1. Selected laboratory results for the elder boy. ### QUESTIONS TO CONSIDER 1. What is the most common cause of a highly increased (>50 μmol/l) homocysteine? 2. Which nutrient deficiencies are associated with increased homocysteine concentrations? 3. What are the deleterious effects of increased plasma homocysteine concentrations? ### HOMOCYSTEINE Homocysteine is a nonessential, non–protein-forming, thiol-containing amino acid that is readily oxidized in the blood to homocystine and other disulfides. Only 1% is found in its free reduced form. The single source of homocysteine in humans is the demethylation of the essential amino acid, methionine, via 2 intermediate compounds, …

Hemiatrophy of the Spinal Cord in a Patient With Mucopolysaccharidosis Type IIIB

The authors describe a girl with mucopolysaccharidosis type IIIB (Sanfilippo disease). She presented with speech delay, macrocephaly, and left lower limb hypoatrophy. Her brain and spinal cord imaging revealed diffuse cystic brain lesions and hemiatrophy of her spinal cord on the left (thoracic levels 11/12). She had marked reduction of her α-N-acetylglucosaminidase activity assay consistent with the diagnosis of mucopolysaccharidosis type IIIB. Mutational analysis showed 2 mutations on exon 6 of the α-N-acetylglucosaminidase gene, both of which were identified in her parents. At 10 years of age the girl had minor learning difficulties and mild behavioral problems. Her spinal cord hemiatrophy, in association with mucopolysaccharidosis type III, has not previously been described in the literature.

The first Case of Riboflavin Transporter Deficiency in Sub-Saharan Africa

This report describes the first case of a child with genetically confirmed Brown-Vialetto-van Laere syndrome in sub-Saharan Africa. This is an extremely rare clinical condition that presents with an auditory neuropathy, bulbar palsy, stridor, muscle weakness, and respiratory compromise that manifests with diaphragmatic and vocal cord paralysis. It is an autosomal recessive condition for which the genetic mutation has only recently been linked to a riboflavin transporter deficiency. We describe an 11-month-old affected male infant. He has required long-term respiratory support and a gastrostomy tube to support feeding. With high-dose riboflavin supplementation, he had limited recovery of motor function. His respiratory chain enzyme studies were abnormal suggestive of mitochondrial (mt) dysfunction. In the setting of limited resources, recognition of this striking clinical phenotype is important to highlight, specifically regarding the genetic implications of the condition and the potentially remedial response to vitamin supplementation.