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Logo of archdischArchives of Disease in ChildhoodVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
Arch Dis Child. 2007 April; 92(Suppl1): A91–A93.
PMCID: PMC2066103


Inherited metabolic disease

G/THUR/MET1 A high diagnostic yield in children attending a metabolic centre with developmental delay

A. Awadalla, E. Treacy, A. Monavari, E. Crushell, S. Harty. Children's University Hospital, Dublin, Ireland

AimsInborn errors of metabolism are reported to be a rare cause (1–5%) (Shevell et al) of developmental delay. The aims are to determine the aetiological yield of metabolic investigation in children referred to a tertiary metabolic service where developmental delay was a primary feature, and to determine the variables that make achieving a diagnosis more likely.

MethodsCases were identified retrospectively from the database at the national centre for inborn errors of metabolism and details obtained from case notes. Referral information, history, examination findings, investigations and diagnosis were studied.

ResultsFifty two cases (31 male, 21 female, and age range 7–175 months) were identified between January 2004 and December 2005. Source of referral were General Paediatrician (33), Paediatric Neurologist (14), General Practitioner (2) and others (3). 13 (25%) patients had a definitive metabolic diagnosis, including 5 (9.6%) that had a diagnosis at referral. A metabolic diagnosis was strongly suspected in a further 6 patients. Definitive diagnoses included: mitochondrial disorder (9), SCAD (1), SCHAD (1), EMA encephalopathy (1), Orotic aciduria (1). Three additional patients were found to have other genetic disorders. Children with a definitive metabolic diagnosis were compared with those in whom no diagnosis was found. Abnormal eye examination (30.7% v 15.6%), microcephaly (25% v 13.7%), seizures (23% v 10%) and referral by a paediatric neurologist (50% v 25.9%) were more likely in patients with a definitive diagnosis. Biochemical markers positively associated with a definitive diagnosis included a high serum lactate (30.7% v 15.6%), abnormal serum amino acids (69.2% v 33.3%) and abnormal urine organic acids (61.5% v 12%). Patients with autistic features were less likely to have a metabolic diagnosis (15% v 34.4%).

ConclusionThe aetiological yield of metabolic testing is significantly higher (25%) in patients with developmental delay than previously reported. Positive indicators include high serum lactate, abnormal serum amino acids and abnormal urine organic acids. Achieving a diagnosis has important implications for management, prognosis and genetic counselling.

G/THUR/MET2 A study on growth in children with classical galactosaemia

J. O'Conor1, C. McDonnell2, J. Hughes1, R. Manning1. 1National Centre for Inherited Metabolic Disease, Dublin, Ireland; 2Department of Endocrinology, Children's University Hospital, Dublin, Ireland

AimTo assess growth in a cohort of individuals with classical galactosaemia.

MethodsA retrospective chart review of all patients with classical galactosaemia aged 18 and over, who attend the National Centre for Inherited Metabolic Diseases. Data gathered included: correct diagnosis, mutational analysis, enzymology, auxology, final height and in the case of females, whether or not they were commenced on HRT and at what age.

ResultsData have been collected and analysed from 32 patients. The cohort analysed consisted of 15 boys and 17 girls. The group's birth weight had a normal distribution. The cohorts BMI Z scores had a mean of −0.69 (range −2.45 to 0.79). Their height Z scores gave a mean of −0.27 (range −1.74 to 1.88). There were no significant differences between males and females.

ConclusionPatients with classical galactosaemia have a lower height and BMI when compared to the normal population. Previous studies in children suggested that girls tend to fare worse, however on reaching final height no significant difference was appreciated here. It remains to be analysed if HRT plays a part in minimising the gender difference. As some of the long‐term complications in classical galactosaemia are believed to be due to a secondary glycosylation defect, which interferes with hormone synthesis, we postulate that patients with classical galactosaemia, should be considered for hormone replacement therapy.

G/THUR/MET3 Phenotypic/genotypic correlation in glycogen storage disease type IX

N. Beauchamp1, A. Dalton2, S. Tanner1, M. Sharrard2. 1University of Sheffield, Sheffield, UK; 2Sheffield Children's NHS Foundation Trust, Sheffield, UK

BackgroundThe severity of symptoms associated with glycogen storage disease type IX (GSD IX) varies from hepatomegaly alone to liver disease, hypoglycaemia, seizures, short stature and muscle hypotonia. GSD IX results from a deficiency of the multi‐subunit phosphorylase kinase and can be either X linked (PHKA2 gene) or autosomal recessive (PHKB or PHKG2 genes).

AimCharacterise mutations in GSD IX patients and correlate with phenotype.

Patients and MethodsAmong the 143 patients investigated for GSD were 45 GSD IX patients analysed for mutations in at least one of the three genes. All exons of each gene were amplified by PCR and directly sequenced.

ResultsTwenty patients had mutations in PHKA2, three mutations in PHKB and three had mutations in the PHKG2 gene. Two patients were diagnosed with GSD 6 or 0 by further genetic analysis. Of the 18 different PHKA2 mutations, 5 had been reported previously, 2 resulted in frameshifts (p.I337fs, p.I1161fs) and there was one each of duplication (p.116‐120dup5), deletion (p.R1070del), nonsense (p.R392X) and splice site (c.3336+1G>T) mutations. There were seven missense mutations (p.R45W, p.R45Q, p.P498L, p.P869R, p.R916W, p.G1075E, p.M1113I). The majority of these clustered towards the termini of the protein. Two patients with missense mutations p.P498L and p.P869R outside these clusters did not have hepatomegaly and only rarely had hypoglycaemia. Patients with null alleles generally had a more severe phenotype with hepatomegaly, short stature and liver dysfunction. Five mutations in PHKB were identified in three patients. One patient with a very mild phenotype was heterozygous for a single novel p.M185I mutation. A moderately severe phenotype was observed in 2 compound heterozygous patients who carried a novel mutation each (c.1207+1G>T, c.2337‐2A>C). Three patients with a severe phenotype were homozygous for novel mutations in the PHKG2 gene (c.96‐11G>A, p.H48fs and p.L144P).

ConclusionsAlthough numbers are small, the results suggest patients with missense mutations in PHKA2 and PHKB have a milder phenotype to patients with null alleles. Patients with mutations in PHKG2 have the most severe clinical features. Molecular analysis of PHKA2, PHKB and PHKG2 is useful in investigating patients with hypoglycaemia, hepatomegaly and hepatopathy.

G/THUR/MET4 A case of glycogen storage disease type IXc and insulin dependent diabetes mellitus

J. Abraham1, L. Al Nakib2, A. Massoud2, J. Raiman1. 1Department of Paediatric Metabolic Medicine, Evelina Children's Hospital, Guy's and St Thomas NHS Trust, London, UK; 2Department of Paediatrics, Northwick Park Hospital, Middlesex, UK

BackgroundGlycogen storage disease (GSD) type IXc is the autosomal recessive form of phosphorylase kinase deficiency, caused by mutations of the PHKG2 gene, encoding the catalytic gamma subunit of the testis/liver isoforms. This result in a more severe phenotype than the commoner X linked form, GSD type IXa.

Case StudyWe present a 7‐year‐old boy referred to us with hepatomegaly and growth faltering. Previous investigation outside of the UK had led to a presumptive diagnosis of a GSD at 2 years of age, though no further intervention had occurred. At presentation he was symmetrically small, weight 2nd–9th %/height <0.4th %. The liver was enlarged to 10 cm and spleen to 4 cm below the costal margins. Initial investigations included elevated AST 568 IU/l, GGT 357 IU/l, lactate 6 mmol/l, cholesterol 16.6 mmol/l and triglycerides 10 mmol/l His fasting tolerance was <6 h. Red blood cell glycogen was increased at 1001 μg/g Hb (10–120) and the phosphorylase a/total phosphorylase ratio was abnormal, suggestive of a defect in the phosphorylase activating system. Molecular analysis revealed homozygosity for base pair change c.431T>C in the PHKG2 gene. This leads to a p.L144P substitution in a highly conserved region of the amino acid sequence. He showed a dramatic response to the institution of nasogastric feeding with rapid catch up growth. However 6 months after starting therapy, following a brief history of weight loss, polydispia and polyuria, a diagnosis of IDDM was made. At that stage a blood sugar was elevated at 27 mmol/l with concurrent profound ketonuria. Subsequent management of both conditions has proven very challenging in balancing the metabolic nutritional requirements of his GSD while optimising his diabetic control. He has now stabilised with the use of a continuous subcutaneous insulin pump and has begun to show his previous catch up growth.

ConclusionDiabetes has been described as late complication of GSD types Ib and III. Liver glycogenosis has also been reported as a complication of poorly controlled IDDM previously. Our case appears to be the first reported case of GSD IX and IDDM, which may reflect the severity of the IXc phenotype. Other possible common aetiological factors and the management issues will be discussed.

G/THUR/MET5 Childhood methylmalonic acidaemia: a 30‐year experience

P. Nair, R. Arora, J. Walter. The Wellink Unit, Manchester, Manchester, UK

AimsTo study the clinical course, morbidity and long‐term outcome of children with MMA at a regional paediatric centre.

MethodsRetrospective case‐note review of patients presenting from 1976–2006 to a tertiary referral centre.

ResultsForty three (male 22) children, of whom 74% were of Asian origin, were diagnosed during this period. The median age at diagnosis was 12 weeks (range 2 days–8.5 years). At presentation 58% had feeding difficulties while 21% had failure to thrive, prolonged jaundice, developmental delay and 16% had an acute neurological event or metabolic acidosis. The enzymatic subgroups were mut033% (none B12 responsive), cbl A/B 31% (42% unresponsive and 58% fully/partially responsive to B12) and cdl C/D 18% (all fully/partially responsive to B12). The main morbidities were neurological (developmental delay 79%, movement disorder 21%, stroke 14%, seizure 14%), acute metabolic decompensations 46% and chronic renal failure 23%. Vitamin B12 unresponsiveness was associated with a poorer long‐term outcome and mortality. 25% of our children died at a median age of 13 months (range 2 weeks–15 years) of which 80% were unresponsive to vitamin B12. Importantly all patients diagnosed in the last 10 years are alive.

ConclusionMMA is a chronic disorder with significant morbidity and mortality that is related to vitamin B12 responsiveness. There is also a trend of improvement in mortality over the last 30 years.

G/THUR/MET6 Audit of muscle biopsy in infants under 12 months in a tertiary metabolic/neurology centre

V. McClelland, N. Costin‐Kelly, R. Brown, A. Chakrapani, C. Hendriksz. Birmingham Children's Hospital, Birmingham, UK

AimsThirty per cent of muscle biopsies at our children's hospital are from infants under 12 months old. Infants have often presented with unexplained acute life‐threatening illness and biopsy is requested to seek a metabolic or neuromuscular diagnosis. Samples are analysed according to local and national metabolic network recommendations. We audited the muscle biopsy service for this patient group at this tertiary metabolic centre to ask: are all recommended investigations being completed? Can the service be streamlined?

MethodsRetrospective review of all muscle biopsy reports from patients under 12 months taken from 2002–5.

ResultsTwenty eight biopsies were performed at a mean age of 15 weeks (1–44). Clinical indications included hypotonia (32%), ventilatory requirement (28%), hepatic failure (28%), paucity of movement (21%), acute life threatening event (18%), metabolic acidosis (14%) and abnormal movements (14%). The table shows the tests performed. Five biopsies were diagnostic, showing spinal muscular atrophy (1), cytochrome oxidase deficiency (3) and Niemann Pick C (1). Eight were suggestive and directed further investigations. Two patients were subsequently diagnosed with Leigh's disease and two others had Pol G mutation.

Table thumbnail
Abstract G/THUR/MET6

ConclusionMost recommended tests were completed. Some tests were omitted according to clinical indication. 18% biopsies were diagnostic and 14% contributed to diagnosis by suggesting further investigation. Further streamlining of the service might adversely affect this diagnostic yield.

G/THUR/MET7 Paediatric presentations of complex 1 respiratory chain deficiency in the Irish population

A. Murphy1, E. Crushell1, S. Harty1, R. Manning1, A. Monavari1, E. Treacy2. 1National Centre for Inherited Metabolic Disorders, Temple Street Children's Hospital, Dublin, Ireland; 2Department of Paediatrics, Trinity College, Dublin, Ireland

AimsTo describe the clinical and biochemical features of the cohort of children with respiratory chain deficiency disease due to primary complex 1 deficiency in the Republic of Ireland.

MethodsDatabase and chart review of all patients attending a tertiary referral centre with a diagnosis of complex 1 deficiency confirmed on muscle enzymology during the years 2003–6. Age at presentation, antenatal manifestations, presenting features including the presence of informative biochemical markers, consanguinity and ethnic background were noted.

ResultsTwelve patients (8 male, 4 female) were listed (age range 6 months to 25 years). Seven patients presented in the first year of life but all were symptomatic in their preschool years. Three had evidence of antenatal involvement, 8 presented with a moderate‐severe neurological phenotype, 2 presented with an isolated cardiac phenotype (left ventricular non‐compaction syndrome), 3 presented with apparent life‐threatening events. All patients were from the indigenous Irish population with no history of consanguinity. All patients had at least “mitochondrial biochemical marker” in blood or urine specimens.

ConclusionHereditary mitochondrial disorders are responsible for a wide variety of clinical symptoms in childhood. Birth prevalence in Ireland is estimated at 1 per 4087 during the study period of which 20% have confirmed isolated complex 1 deficiency. Investigation is underway to elucidate the genetic aetiology of complex 1 deficiency in the Irish population.

G/THUR/MET8 Short chain acyl‐coenzyme a dehydrogenase deficiency: a clinical chameleon

J. O'Conor1, J. Hughes1, B. Lynch2, R. Manning1, A. A. Monavari1. 1The National Centre for Inherited Metabolic Disorders, Dublin, Ireland; 2Department of Neurology, Children's University Hospital, Temple Street, Dublin, Ireland

AimTo report a series of 5 new patients with short chain acyl‐Coenzyme A (CoA) dehydrogenase deficiency SCADD. All had mutations other than the common polymorphisms.

CasesCase 1 presented as a neonate with vomiting and hyperbilirubinaemia. Work‐up revealed elevated ethylmalonic acid and methylsuccinate on urine organic acids. acylcarnitine profiling revealed elevated butyrylcarnitine, suggestive of SCADD. This was confirmed on enzyme activity. Mutation analysis revealed two mutations in the SCAD gene: 578C>T and 815G>A. Case 2 a younger sibling of case 1, was noted to have elevated ethylmalonic acid and methylsuccinate on urine organic acids though asymptomatic. Further testing confirmed elevated butyrylcarnitine, reduced SCAD activity in fibroblasts and the same gene mutations as his brother. Both boys remained asymptomatic. Case 3 presented at 4 weeks with mycoplasma encephalitis. Investigation revealed elevated ethylmalonic acid and methylsuccinate in urine organic acids. He later developed seizures and displayed some developmental regression. Mutation analysis has revealed two mutations: the common polymorphism 625G>A and 418A>G. Enzymology confirmed SCADD in fibroblasts. Case 4 presented at 7 months with a history of increasing seizure activity. Firstborn to consanguineous parents, he was noted to have a markedly abnormal neurological examination and EEG. Investigation revealed raised ethylmalonic aciduria with moderately raised 3‐methylglutaconicaciduria. MRI brain was abnormal and raised lactate was detected on brain MRS. Fatty acid oxidation flux in fibroblasts was reduced with a significant elevation of butyrylcarnitine. He is homozygous for a gene variant 1095G>Tin the SCAD gene. Enzymology studies are ongoing. He died at 10 months of age. Case 5 presented with recurrent chest infections in early life. Investigation revealed abnormal urinary organic acids with raised ethylmalonic acid, methylmalonic acid and methylsuccinate. Subsequent investigation showed an elevated butyrylcarnitine in fibroblasts. Enzymology has confirmed reduced SCAD activity in fibroblasts. Mutation analysis is ongoing.

ConclusionsThese five cases confirm the variable nature of the presentation of SCADD. Presentation and discussion of cases will help our understanding of this poorly understood disorder.

G/THUR/MET9 Transient hypoglycorrhachia presenting with neonatal apnoea

E. Footitt, J. Eardley, M. Champion. Evelina Children's Hospital, London, UK

BackgroundGLUT 1 deficiency results from a block in facilitated glucose transport across the blood brain barrier due to a defective glucose transporter protein with consequent hypoglycorrhachia in the presence of normoglycaemia (CSF:blood ratio <0.4). Clinical presentation includes seizures, acquired microcephaly and global developmental delay. Seizures are resistant to anticonvulsant medication but respond well to a ketogenic diet. We describe a case of transient hypoglycorrhachia presenting with neonatal apnoea which resolved spontaneously with normalisation of the CSF: blood glucose ratio.

Case StudyA 4‐week‐old girl presented with multiple apnoeic episodes requiring resuscitation. She was born at term following a pregnancy complicated by maternal heroin abuse in the first trimester. The antenatal period was otherwise unremarkable and at delivery she had no clinical withdrawal syndrome and negative urine toxicology screen. There were no clinical concerns until presentation. Examination was unremarkable and investigations showed normal infection parameters with negative blood and CSF cultures. Cranial ultrasound, CT head and MRI brain were normal and EEG during an event showed no epileptiform activity. A pH study showed mild insignificant gastro‐oesophageal reflux. Serial CSF glucose measurements demonstrated persistent hypoglycorrhachia (CSF glucose 1.9, 1.9 and 1.5 mmol/l), the latter was a fasting sample with simultaneous blood glucose 4.1 mmol/l giving a ratio of 0.36. CSF lactate was normal on two occasions (1.3 and 1.2 mmol/l). Due to her young age and the absence of seizures, she was managed conservatively without introducing a ketogenic diet. All symptoms resolved and repeat her lumbar puncture at 4 months of age was normal (CSF glucose 2.5 mmol/l, blood glucose was 4.2 mmol/l, ratio of 0.59). Subsequent development is normal.

ConclusionThis case represents a transient abnormality in GLUT 1 mediated transport across the blood‐brain barrier similar to those described by Klepper (2003) possibly reflecting foetal isoforms. This case highlights that early neonatal hypoglycorrhachia may be transient and the need for repeat assessment of the CSF glucose to differentiate this benign condition from GLUT 1 deficiency which requires lifelong treatment with the ketogenic diet.

Klepperet alPaediatric Neurology29 pp 321-5


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