Retrospective Review of Positive Newborn Screening Results for Isovaleric Acidemia and Development of a Strategy to Improve the Efficacy of Newborn Screening in the UK.

Since the UK commenced newborn screening for isovaleric acidemia in 2015, changes in prescribing have increased the incidence of false positive (FP) results due to pivaloylcarnitine. A review of screening results between 2015 and 2022 identified 24 true positive (TP) and 84 FP cases, with pivalate interference confirmed in 76/84. Initial C5 carnitine (C5C) did not discriminate between FP and TP with median (range) C5C of 2.9 (2.0-9.6) and 4.0 (1.8->70) µmol/L, respectively, and neither did Precision Newborn Screening via Collaborative Laboratory Integrated Reports (CLIR), which identified only 1/47 FP cases. However, among the TP cases, disease severity showed a correlation with initial C5C in 'asymptomatic' individuals (n = 17), demonstrating a median (range) C5C of 3.0 (1.8-7.1) whilst 'clinically affected' patients (n = 7), showed a median (range) C5C of 13.9 (7.7-70) µmol/L. These findings allowed the introduction of dual cut-off values into the screening algorithm to reduce the incidence of FPs, with initial C5C results ≥ 5 µmol/L triggering urgent referral, and those >2.0 and <5.0 µmol/L prompting second-tier C5-isobar testing. This will avoid delayed referral in babies at particular risk whilst reducing the FP rate for the remainder.

Dietary Management, Clinical Status and Outcome of Patients with Citrin Deficiency in the UK.

BACKGROUND: Little is known about the optimal dietary treatment for citrin deficiency. Our aim is to describe the management of UK citrin deficiency patients. METHODS: A longitudinal retrospective review was performed. Data were collected from medical records on presenting signs and symptoms, dietary management and clinical outcome. RESULTS: data were collected on 32 patients from 21 families. 50% were females (16/32). Median age at diagnosis was 4 y (5 days-35 y) with 12 patients diagnosed in the neonatal period with neonatal intrahepatic cholestasis (NICCD), eight later in childhood (FTTDCD) and 12 by family screening based on index cases from five families. No patient had adult-onset type II citrullinemia. The patient age at the time of data collection was a median of 11 y (1-44 y). 91% (29/32) of patients had normal physical and neurological development, 47% (15/32) experienced recurrent unexplained abdominal pain and 9% (3/32) episodes of hypoglycaemia. Siblings had different phenotypes (5 families had > 1 affected patient). Most patients preferred high protein foods, limiting sugar-containing foods. Only 41% (13/32) were prescribed a low CHO, high protein, high fat diet (restriction varied) and two used medium chain triglyceride (MCT) supplements. No patient was prescribed drug therapy. Twenty-five per cent (8/32) of patients were underweight and 41% (13/32) had height <-1 z-scores. CONCLUSIONS: patients presented with various phenotypes, symptoms and suboptimal growth. Symptoms and biochemical markers improved with age, but height remained low in some. More research is necessary to assess the effectiveness of dietary approaches in improving clinical outcomes and symptoms in citrin deficiency.

The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency.

PURPOSE: Mitochondrial DNA (mtDNA) depletion syndrome (MDDS) encompasses a group of genetic disorders of mtDNA maintenance. Mutation of RRM2B is an uncommon cause of infantile-onset encephalomyopathic MDDS. Here we describe the natural history of this disease. METHODS: Multinational series of new genetically confirmed cases from six pediatric centers. RESULTS: Nine new cases of infantile-onset RRM2B deficiency, and 22 previously published cases comprised a total cohort of 31 patients. Infants presented at a mean of 1.95 months with truncal hypotonia, generalized weakness, and faltering growth. Seizures evolved in 39% at a mean of 3.1 months. Non-neurological manifestations included respiratory distress/failure (58%), renal tubulopathy (55%), sensorineural hearing loss (36%), gastrointestinal disturbance (32%), eye abnormalities (13%), and anemia (13%). Laboratory features included elevated lactate (blood, cerebrospinal fluid (CSF), urine, magnetic resonance (MR), spectroscopy), ragged-red and cytochrome c oxidase-deficient fibers, lipid myopathy, and multiple oxidative phosphorylation enzyme deficiencies in skeletal muscle. Eight new RRM2B variants were identified. Patients with biallelic truncating variants had the worst survival. Overall survival was 29% at 6 months and 16% at 1 year. CONCLUSIONS: Infantile-onset MDDS due to RRM2B deficiency is a severe disorder with characteristic clinical features and extremely poor prognosis. Presently management is supportive as there is no effective treatment. Novel treatments are urgently needed.

Monocarboxylate transporter 1 deficiency and ketone utilization.

Ketoacidosis is a potentially lethal condition caused by the imbalance between hepatic production and extrahepatic utilization of ketone bodies. We performed exome sequencing in a patient with recurrent, severe ketoacidosis and identified a homozygous frameshift mutation in the gene encoding monocarboxylate transporter 1 (SLC16A1, also called MCT1). Genetic analysis in 96 patients suspected of having ketolytic defects yielded seven additional inactivating mutations in MCT1, both homozygous and heterozygous. Mutational status was found to be correlated with ketoacidosis severity, MCT1 protein levels, and transport capacity. Thus, MCT1 deficiency is a novel cause of profound ketoacidosis; the present work suggests that MCT1-mediated ketone-body transport is needed to maintain acid-base balance.

Unilateral periventricular leukomalacia in association with pyruvate dehydrogenase deficiency.

Pyruvate dehydrogenase (PDH) deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. A deficiency of PDH E1 alpha, a subunit of the PDH complex, is a prominent cause of congenital lactic acidosis. We describe a female infant born at term and delivered by emergency Caesarean section because of fetal distress. There was no parental consanguinity. She presented at 5 months of age with failure to thrive, microcephaly, hypertonia, and developmental impairment. Her plasma and cerebrospinal fluid lactate were raised. She had raised plasma pyruvate with a normal lactate-pyruvate ratio. Magnetic resonance imaging of the brain showed a focal dilatation of the right lateral ventricle with unilateral periventricular leukomalacia (PVL) with subependymal cyst. Skin fibroblast culture assay revealed PDH deficiency, confirmed by mutation analysis of the E1 alpha subunit. At 18 months of age, she has hypertonia and global impairment and is making slow progress. Denver II assessment showed delay in gross motor, fine motor, adaptive, personal, social, and language categories. She has been treated with dichloroacetate and a ketogenic diet since the age of 10 and 13 months respectively, without any side effects. To our knowledge, unilateral PVL as a neuroradiological feature has not been described in children with PDH deficiency. PDH deficiency should be considered as a differential diagnosis if PVL is unilateral and if the perinatal history is not typical of PVL.

Riboflavin-responsive trimethylaminuria in a patient with homocystinuria on betaine therapy.

A 17-year-old female patient with pyridoxine non-responsive homocystinuria, treated with 20 g of betaine per day, developed a strong body odour, which was described as fish-like. Urinary trimethylamine (TMA) was measured and found to be markedly increased. DNA mutation analysis revealed homozygosity for a common allelic variant in the gene coding for the TMA oxidising enzyme FMO3. Without changing diet or betaine therapy, riboflavin was given at a dose of 200 mg per day. An immediate improvement in her odour was noticed by her friends and family and urinary TMA was noted to be greatly reduced, although still above the normal range.Gradual further reductions in TMA (and odour) have followed whilst receiving riboflavin. Throughout this period, betaine compliance has been demonstrated by the measurement of dimethylglycine (DMG) excretion, which has been consistently increased. Marked excretions of DMG when the odour had subsided also demonstrate that DMG was not the source of the odour.This patient study raises the possibility that betaine may be converted to TMA by intestinal flora to some degree, resulting in a significant fish odour when oxidation of TMA is compromised by FMO3 variants. The possibility exists that the body odour occasionally associated with betaine therapy for homocystinuria may not be related to increased circulating betaine or DMG, but due to a common FMO3 mutation resulting in TMAU. Benefits of riboflavin therapy for TMAU for such patients would allow the maintenance of betaine therapy without problematic body odour.

The use of MR imaging and spectroscopy of the brain in children investigated for developmental delay: what is the most appropriate imaging strategy?

OBJECTIVES: Developmental delay is a common problem in paediatric practice and many children with developmental delay are referred for MR imaging. Our study was performed as part of a continuing audit process to optimise our MR protocol and case selection. MATERIALS AND METHODS: We performed MR imaging and spectroscopy protocol on 157 children with developmental delay. We analysed the effect of these interventions by looking at the overall detection rate of relevant pathology and in particular subgroups of the children. RESULTS: 71% of the children had normal MR imaging, 10% had non-specific findings and 19% had specific abnormalities on MR imaging. The overall risk of having a specific structural abnormality with isolated developmental was 7.5% but if other neurological symptoms/signs were present the risk was 28%. Two children had abnormal spectroscopic findings, one with tuberous sclerosis and the other with absent brain creatine. CONCLUSION: Case selection for MR imaging is important in children with developmental delay. The best strategies for selecting children for MR are either; not performing MR with developmental delay in one domain only or performing MR with developmental delay in three or four domains or if there are other neurological features.

Glycogen storage disease type IX: High variability in clinical phenotype.

Glycogen storage disease type IX (GSD type IX) results from a deficiency of hepatic phosphorylase kinase activity. The phosphorylase kinase holoenzyme is made up of four copies of each of four subunits (alpha, beta, gamma and delta). The liver isoforms of the alpha-, beta- and gamma-subunits are encoded by PHKA2, PHKB and PHKG2, respectively. Mutation within these genes has been shown to result in GSD type IX. The diagnosis of GSD type IX is complicated by the spectrum of clinical symptoms, variation in tissue specificity and severity, and its inheritance, either X-linked or autosomal recessive. We investigated 15 patients from 12 families with suspected GSD type IX. Accurate diagnosis had been hampered by enzymology not being diagnostic in five cases. Clinical symptoms included combinations of hypoglycaemia, hepatosplenomegaly, short stature, hepatopathy, weakness, fatigue and motor delay. Biochemical findings included elevated lactate, urate and lipids. We characterised causative mutations in the PHKA2 gene in ten patients from eight families, in PHKG2 in two unrelated patients and in the PHKB gene in three patients from two families. Seven novel mutations were identified in PHKA2 (p.I337X, p.P498L, p.P869R, p.Y116_T120dup, p.R1070del, p.R916W and p.M113I), two in PHKG2 (p.L144P and p.H48QfsX5) and two in PHKB (p.Y419X and c.2336+965A>C). There was a severe phenotype in patients with PHKG2 mutations, a mild phenotype with patients PHKB mutations and a broad spectrum associated with PHKA2 mutations. Molecular analysis allows accurate diagnosis where enzymology is uninformative and identifies the pattern of inheritance permitting counselling and family studies.

Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway.

We present the first two identified cases of phosphoserine aminotransferase deficiency. This disorder of serine biosynthesis has been identified in two siblings who showed low concentrations of serine and glycine in plasma and cerebrospinal fluid. Clinically, the index patient presented with intractable seizures, acquired microcephaly, hypertonia, and psychomotor retardation and died at age 7 mo despite supplementation with serine (500 mg/kg/d) and glycine (200 mg/kg/d) from age 11 wk. The younger sibling received treatment from birth, which led to a normal outcome at age 3 years. Measurement of phosphoserine aminotransferase activity in cultured fibroblasts in the index patient was inconclusive, but mutational analysis revealed compound heterozygosity for two mutations in the PSAT1 gene--one frameshift mutation (c.delG107) and one missense mutation (c.299A-->C [p.Asp100Ala])--in both siblings. Expression studies of the p.Asp100Ala mutant protein revealed a V(max) of only 15% of that of the wild-type protein.

Magnetic resonance spectroscopy changes following haemopoietic stem cell transplantation in children with cerebral adrenoleukodystrophy.

X-linked cerebral adrenoleukodystrophy is an aggressive, rapidly progressive disorder resulting in considerable morbidity and, left untreated, mortality. Patients typically present before the age of 10 years with progressive symptomatology including ataxia, spasticity, and focal neurological deficits. Current therapeutic options are limited, the treatment of choice being haemopoietic stem cell transplantation (HSCT). Intervention is beneficial to those children with early disease and characteristic magnetic resonance (MR) imaging changes. Developments in MR imaging have led to the incorporation of MR spectroscopy in the assessment tools; however, it is yet to be included in stratified assessment tools to guide treatment choice. Furthermore, there remains a paucity of outcome data on MR spectroscopy changes following HSCT. We describe our experience in two males with confirmed cerebral adrenoleukodystrophy treated, at the mean age of 5 years 6 months, with HSCT and report the pronounced spectroscopic changes observed following treatment. Both children, observed for a minimum period of 14 months following treatment, demonstrate complete reversal in previously deteriorating spectroscopy with marked increase in N-acetyl-aspartate (NAA)/choline (Cho) ratios and reduction in Cho/creatine (Cr) ratios following HSCT treatment with concomitant stabilization of clinical status.

Acute bilateral striatal necrosis with rotavirus gastroenteritis and inborn metabolic predisposition.

We present a 9-month-old male with acute rotavirus gastroenteritis who developed an acute encephalopathy with focal seizures and developmental regression. Magnetic resonance imaging showed bilateral striatal necrosis and raised glutarylcarnitine levels on tandem mass spectrometry of a (crisis) blood spot, and chromatography of organic acids revealed increased urinary excretion of dicarboxylic acid. Skin biopsy demonstrated a partial decrease in glutaryl-CoA dehydrogenase activity. The case was not typical for either rotavirus encephalitis/rotavirus-associated encephalopathy or for glutaric aciduria type I. The patient has developmental delay and continues to receive physiotherapy, speech therapy, and local developmental follow-up.

Massive subdural haematomas in Menkes disease mimicking shaken baby syndrome.

INTRODUCTION: Menkes disease is an X-linked inherited disorder of intestinal copper absorption resulting in copper deficiency. Cardinal features include hair abnormalities, facial dysmorphism, severe neurological impairment, hypothermia, arterial anomalies, bone abnormalities and a fatal outcome. CASE REPORT: We present a case of Menkes disease complicated by progressive macrocephaly following the development of massive subdural haematomas. These lesions associated with femoral metaphyseal spurs could be confused with nonaccidental injury such as that seen in the shaken baby syndrome. DISCUSSION: This case emphasises that Menkes disease, like glutaric aciduria type 1, should be included in the differential diagnosis of unexplained subdural haematomas and neurological deficits in infants.