Increased ocular wall thickness and decreased globe volume in children with mucopolysaccharidosis type VI.

PURPOSE lthough clinical ophthalmologic findings have been reported, no study documented magnetic resonance imaging (MRI) findings in mucopolysaccharidosis (MPS) type VI. The aim of this study was to determine the ophthalmologic imaging findings of MPS type VI in the pediatric age group retrospectively. METHODS Brain MRIs of 10 patients with MPS type VI and 49 healthy children were evaluated independently by two pediatric radiologists for the following characteristics: globe volume, ocular wall thickness, and optic nerve sheath diameter for each orbit. The means of the measurement of each group were compared by using an independent t-test. Agreement and bias between reviewers were assessed by intra-class correlation coefficients (ICC). RESULTS A total of 59 children [32 girls (54.23%), 27 boys (45.77%); age range, 4-16 years; mean age, 10.37 ± 3.73 years] were included in the study. Statistical analysis revealed smaller eyeballs and thicker ocular walls of patients with MPS type VI (P < .001 and P < .001, respectively). However, there was no statistically significant difference in terms of optic nerve sheath diameter between the two groups (P=.648). CONCLUSION Patients with MPS type VI displayed reduced globe volumes and increased ocular wall thicknesses compared to the healthy children. Therefore, we recommend that ophthalmologic imaging findings might prove to be an auxiliary tool in the diagnosis of MPS patients.

A late-diagnosed phenylketonuria case presenting with autism spectrum disorder in early childhood.

Phenylketonuria is one of the most prevalent autosomal recessive hereditary disorders in Turkey. If untreated, it results in severe brain damage and can also be associated with autism in certain patients. We present a three-year old boy who exhibited the symptoms of autism and was subsequently diagnosed with phenylketonuria. This case illustrates that because the majority of autism cases are idiopathic, an occasional patient with a metabolic disorder might be overlooked especially in the era of newborn screening. We also discuss the possible pathogenetic processes leading to autistic symptoms in phenylketonuria, and wish to draw attention to the possibility of cases missed in the screening program because of less than 100% coverage or insufficient food intake before blood sampling. Clinicians should keep in mind the possibility of treatable disorders in children with autism even when such disorders appear unlikely.

Novel Mutations in the PC Gene in Patients with Type B Pyruvate Carboxylase Deficiency.

We have investigated seven patients with the type B form of pyruvate carboxylase (PC) deficiency. Mutation analysis revealed eight mutations, all novel. In a patient with exon skipping on cDNA analysis, we identified a homozygous mutation located in a potential branch point sequence, the first possible branch point mutation in PC. Two patients were homozygous for missense mutations (with normal protein amounts on western blot analysis), and two patients were homozygous for nonsense mutations. In addition, a duplication of one base pair was found in a patient who also harboured a splice site mutation. Another splice site mutation led to the activation of a cryptic splice site, shown by cDNA analysis.All patients reported until now with at least one missense mutation have had the milder type A form of PC deficiency. We thus report for the first time two patients with homozygous missense mutations with the severe type B deficiency, clinically indistinguishable from other patients with type B form of PC deficiency.The mutations found here are novel; it is noteworthy that four Turkish patients did not have any mutations in common, despite the rarity of PC deficiency. There is thus no evidence for recurrent mutations in the Turkish or other populations.

A Patient With Pyruvate Carboxylase Deficiency and Nemaline Rods on Muscle Biopsy.

Nemaline rods are the pathologic hallmark of nemaline myopathy, but they have also been described as a secondary phenomenon in a variety of other disorders. Nemaline rods have not been reported in pyruvate carboxylase deficiency before. Here we present a patient with pyruvate carboxylase deficiency and nemaline rods detected on muscle biopsy. The nemaline rods may be due to cellular energy shortage and altered energy metabolism in pyruvate carboxylase deficiency, similar to that in the previously reported patients. The mechanism of nemaline rod formation may be associated with the role of pyruvate carboxylase in cellular energy pathways.

Vanishing White Matter With Hepatomegaly and Hypertriglyceridemia Attacks.

Vanishing white matter disease is one of the most prevalent leukodystrophies in childhood. It is caused by mutations in any of the genes encoding the 5 subunits of the eukaryotic translation initiation factor 2B (eIF2B), EIF2B1 through EIF2B5. Phenotypic variation is wide and it may affect people of all ages. Here we present a child with vanishing white matter who had hepatomegaly and hypertriglyceridemia attacks along with neurologic deterioration episodes. He was found heterozygous for the 2 mutations c.817 A>C, p.Lys273Gln and c.939_948del, p.Asp314ProfsX23 in the gene EIF2B2. Until today, this association was not defined in the literature.

Home visits in phenylketonuria: a 12-month longitudinal study.

This study aimed to evaluate the effect of dietary education given to the caregivers of children with phenylketonuria (PKU) in their home environment on children's blood phenylalanine (Phe) levels. Thirty-six children with PKU, aged 2-12 years, were recruited. Each caregiver was visited on three separate occasions and given a detailed dietary education. Fasting morning skin puncture blood samples were collected on Newborn Screening Blood Test filter paper for Phe analysis at baseline and 1, 4, 12, 24, and 48 weeks after the home visits. The mean baseline blood Phe level (365 +/- 232 micromol/L) significantly decreased with home visits at the 1st week (314 +/- 226 micromol/L) (p < 0.05). Four weeks after the home visits, the median blood Phe level was still lower than baseline, but the difference was not statistically significant (p > 0.05). The mean blood Phe levels significantly increased at the end of the 12th, 24th and 48th weeks (329 +/- 230 micromol/L; 447 +/- 189 micromol/L and 486 +/- 261 micromol/L, respectively) (p < 0.05). A well-controlled blood Phe level can be achieved with intense, regular and continuing education programs, which include regular home visits.

Four novel PDHA1 mutations in pyruvate dehydrogenase deficiency.

The pyruvate dehydrogenase (PDH) complex is a mitochondrial multienzyme that catalyses the irreversible oxidative decarboxylation of pyruvate to acetyl-CoA. We report four novel PDHA1 mutations in patients with pyruvate dehydrogenase deficiency. Analysis of PDH activity showed decreased activity in fibroblasts from all four patients, around 16-52% of mean control, similar to what has been found in previous studies. Two of the mutations were missense mutations: c.616G>A (p.Glu206Lys) and c.457A>G (p.Met153Val), one was a 3 bp in-frame deletion: c.429_431delAGG (p.Gly143del), and one was a 65 bp duplication: c.900-6_958dup65. cDNA analysis of the 65 bp duplication showed a small amount of normal transcript in addition to the transcript corresponding to the duplication. The small amount of normal transcript likely explains the survival of the patient, who was a boy. The duplication and one of the missense mutations were associated with decreased amounts of E(1)α And E(1)ß protein on western blot analysis, whereas the other two mutations were associated with normal amounts. This study adds four novel mutations to the around 90 reported mutations in PDHA1 (HGMD PDHA1 mutation database). The phenotypes of patients with PDH deficiency have been divided into three groups: a neonatal form with severe lactic acidosis, a form observed only in males and characterized by episodes of ataxia with relapses associated with hyperlactataemia, and an infantile form with hypotonia, lethargy, onset of seizures or dystonia, psychomotor retardation, in some cases Leigh-like lesions and mild to moderate hyperlactataemia. The four patients reported here all belong to the latter group, which is the largest.

Acetaminophen-induced hepatotoxicity in a glutathione synthetase-deficient patient.

We report a patient with glutathione synthetase (GS) deficiency who developed acetaminophen-induced hepatotoxicity after a two-day treatment with regular doses of acetaminophen. A nine-month-old female was referred because of intractable metabolic acidosis. She was given acetaminophen at therapeutic doses over a 48-hour period. She was hospitalized because of confusion and metabolic acidosis. Liver function tests were abnormal with normal bilirubin levels. The urine gas chromatography-mass spectrometry (GC/MS) showed massive excretion of 5-oxoproline. She improved and liver function tests normalized in the next six days, but compensated metabolic acidosis and massive 5-oxoprolinuria persisted. The analysis of GS in erythrocytes revealed 5% of normal enzyme activity, and the patient had 491G > A mutation on both alleles in the GS gene. In this report it can be assumed that patients, even if heterozygous for a mutation of the GS gene, are at risk for acetaminophen toxicity.