Introduction

CAH is an inherited disorder of steroidogenesis with a wide spectrum of expression. In about 95% of cases the condition is the result of 21-hydroxylase deficiency, an autosomal recessive condition mapping to CYP21A2 on chromosome 6p21.3. The incidence of CAH based on biochemical criteria is 1 in 14,000 including the non-classical form; a carrier frequency of 1 in 50 is used for risk calculations.

Referral information

We accept referrals for mutation scanning to confirm a clinical diagnosis in affected patients and/or parents. We offer prenatal diagnosis once the familial mutation(s) are known. This usually follows fetal sexing (which can be offered using conventional or non-invasive prenatal diagnosis – see service profile). In addition we can offer carrier testing in at-risk family members.

View full test details for Congenital Adrenal Hyperplasia (CAH)

Introduction

Fabry disease is an X-linked recessive lipid storage disorder caused by a deficiency of the lysosomal enzyme alphagalactosidase A. This deficiency results in the gradual accumulation of ceramide trihexoside in the walls of the blood vessels and tissues such as the heart, kidneys, and brain, which causes progressive damage and potentially life-threatening problems. Fabry disease is a multisystemic disorder characterised by pain in the extremities in the teens, angiokeratoma, and, in later life, renal disease and stroke. There is a broad spectrum of disease severity, and both cardiac and renal variants have been described. Due to X-linked recessive inheritance, males are more often affected with Fabry disease than females. However, females who are carriers of this disorder often have symptoms ranging from mild or late-onset to severe and this may depend in part on the randomness of X-inactivation and occasionally skewed X-inactivation.  Females can be asymptomatic. The GLA gene is located on Chromosome Xq22. Mutations in GLA result in enzyme deficiency and the subsequent development of Fabry Disease.

Referral information

This service is funded by the National Commissioning Group (NCG). Samples received from England, Northern Ireland and Scotland are charged to the NCG with the majority of samples being received from The Willink Metabolic Unit. New patients are initially diagnosed by enzyme analysis; therefore patients will usually have already been referred to a relevant NCG centre before DNA analysis is requested. Funding from the NCG also covers carrier detection, by DNA analysis, for family members.

View full test details for Fabry Disease

Introduction

Gaucher disease is an autosomal recessive lipid storage disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase. This deficiency results in the accumulation of glucocerebroside. Gaucher disease is a multisystemic disorder characterised by haematological disorders, hepatosplenomegaly, and skeletal disease, and, in more severe forms, neurological deterioration. There is a broad spectrum of disease severity but this can be divided into 3 disease sub-types according to disease symptoms. • Non-neuronopathic (Type I) Gaucher Disease – characterised by anaemia, hepatosplenomegaly and bone disease but without neurological symptoms. • Acute neuronopathic (Type II) Gaucher Disease – these patients show profound brain impairment and usually die before the age of 2 years. • Chronic neuronopathic (Type III) Gaucher disease – characterised by anaemia, massive hepatosplenomegaly, bone disease and neurological symptoms such as horizontal supranuclear gaze palsy. Gaucher disease is caused by mutations in the GBA gene, which encodes for the enzyme glucocerebrosidase. GBA is located on chromosome 1q21. A number of common mutations exist, particularly in the Ashkenazi Jewish population, but many are unique to the family and include a variety of point mutations, deletions, and splice junction defects. There is a highly homologous pseudogene which is situated 16Kb downstream from the functional gene. Rearrangements between the functional and the pseudogene can also introduce mutations.

Referral information

This service is funded by the National Commissioning Group (NCG). Samples received from England, Northern Ireland and Scotland are charged to NCG with the majority of samples being received from The Willink Metabolic Unit. New patients are initially diagnosed by enzyme analysis, therefore patients will usually have already been referred to a relevant NCG centre before DNA analysis is requested. Funding from the NCG also covers carrier detection, by DNA analysis, for family members.

View full test details for Gaucher Disease

Introduction

I-cell disease (also called mucolipidosis II/lll αβ, MLII/lllαβ) is an autosomal recessive disorder caused by a deficiency of the membrane bound enzyme UDP-N –acetylglucosamine- 1-phosphotransferase. The GNPTAB gene encodes two out of three subunits of this enzyme; a heterohexameric complex of two alpha, two beta, and two gamma subunits. The encoded protein is proteolytically cleaved to yield mature alpha and beta polypeptides while the gamma subunits are the product of a distinct gene (GNPTG). Mutations in the GNPTAB gene prevents appropriate trafficking of lysosomal enzymes and thus prevent normal processing. One unique feature of this disease is the presence of phase-dense intracytoplasmic inclusions in the fibroblasts of patients. These cells are termed inclusion cells, or I-cells, thus, the disease is designated I-cell disease. Individuals with more severe features have ML IIαβ; those with less severe, or attenuated, features have ML IIIαβ. I-cell disease is characterized by severe psychomotor retardation that rapidly progresses leading to death between 5 and 8 years of age. Although there are similar signs and symptoms, the earlier onset of symptoms and the lack of mucopolysacchariduria distinguish I-cell disease from Hurler syndrome (MPSl). The GNPTAB gene is located on chromosome 12q23.3.

Referral information

This service is funded by the National Commissioning Group (NCG). Samples received from England, Northern Ireland and Scotland are charged to NCG with the majority of samples being received from The Willink Metabolic Unit. New patients are initially diagnosed by enzyme analysis, therefore patients will usually have already been referred to a relevant NCG centre before DNA analysis is requested. Funding from the NCG also covers carrier detection, by DNA analysis, for family members.

View full test details for I cell disease (MLll/lll αβ)

Introduction

Krabbe Disease is an autosomal recessive inherited disorder affecting myelin in the peripheral and central nervous system. Although the most common form of the disease is the classic fatal severe infantile form (classic Krabbe disease), later onset forms have also been described and up patients up to 50 years have been diagnosed.All patients are deficient in galactocerebrosidase,(GALC) the lysosomal enzyme responsible for the hydrolysis of important glycolipids Assays of GALC activity in leukocytes or cultured fibroblasts with use of appropriate natural glycolipid substrates can establish a diagnosis. . One mutation a 30kb deletion makes up over 50% of mutant alleles in patients from most of northern Europe.

Referral information

We accept referrals from patients with Krabbe disease ie. have a biochemically measured deficiency of galactocerebrosidase also parents and siblings of the index case for carrier testing .NB  Whole gene screening for GALC is not available in this laboratory.

View full test details for Krabbe Disease

Introduction

Defects in Trifunctional enzyme subunit alpha (HADHA gene) are the cause of long-chain 3-hydroxyl-CoA dehydrogenase deficiency (LCHAD deficiency) Biochemically, LCHAD deficiency is characterized by reduced long-chain 3-hydroxyl-CoA dehydrogenase activity, while the other enzyme activities of the Trifunctional protein complex are normal or only slightly reduced. There is considerable heterogeneity in LCHAD deficiency, including fulminant hepatic disease, hypertrophic cardiomyopathy and in some patients unusual features such as progressive neuropathy and pigmentary retinopathy. Most patients with LCHAD deficiency present with signs of fasting induced hypoketotic hypoglycemia. During pregnancy, mothers of affected infants can develop acute fatty liver of pregnancy or hypertension, elevated liver enzymes and low platelets (HELLP) syndrome. The common missense mutation c.1528G&gt;C in LCHAD deficiency accounts for 87% of mutant alleles in patients with LCHAD.<

Referral information

We accept referrals from patients with hypoglycaemia and post mortem SUDI (sudden unexpected death of an infant) samples. Women who are carriers of LCHAD are at risk for pregnancy complications such as HELLP syndrome and acute fatty liver of pregnancy (AFLP) if the unborn child is affected with LCHAD and so we accept maternal samples from such pregnancies. We can also offer this mutation testing for at risk family members and carrier testing.

View full test details for LCHAD Deficiency

Introduction

MCAD deficiency (a fatty acid oxidation defect) is the most common defect in the pathway of mitochondrial beta-oxidation.The most frequent presentation is episodic hypoketotic hypoglycaemia provoked by fasting and beginning in the first 2 years of life. Accumulation of fatty acid intermediates results in plasma and urinary metabolites, some of which are general indicators of impaired function of the Beta -oxidation pathway (e.g. dicarboxylic acids), while others are unique and characteristic of MCAD deficiency Patients with MCAD deficiency can appear normal, but in some cases, the first episode is fatal and can resemble sudden infant death syndrome (SIDS) .Diagnosis can be made by analysis of plasma acylcarnitines or urinary acylglycines or by molecular analysis. The common mutation c.985A>G accounts for >87% of mutant alleles in Europeans.

Referral information

We accept referrals from patients with hypoglycaemia, follow up samples from new born screening and post mortem SUDI (sudden unexpected death of an infant) samples. We can also offer this mutation testing for at risk family members and carrier testing.

View full test details for Medium Chain Acyl-CoA Dehydrogenase Deficiency MCADD

Introduction

We offer a next generation sequencing mutation scan, including an interpretation of variants found, of genes (please see below for a full list) focussing on inborn errors of metabolism that primarily affect the nervous system. The FULL metabolic panel contains 226 genes involved in 11 areas of clinical/biochemical indication (see Key below) divided into 6 sub-panels (see table below) based these groups of disorders.

Referral information

We offer mutation scanning in affected individuals and obligate carriers. This testing is relevant for sporadic cases or patients with a family history consistent with an autosomal dominant, recessive or X-linked family history of a metabolic disorder.  On identification of a pathogenic change in an index case presymptomatic and carrier testing of relatives of an index case can be offered. Referrals should be accompanied with a completed clinical proforma indicating which panels are required ( FULL or a combination of 1 or more sub panels) Referrals also should be accompanied by a completed standard referral request form. For optimal results please send a fresh EDTA blood sample (1-4ml) or a minimum of 3 microgrammes of extracted DNA.

Key:  AA Disorders of amino acid metabolism including phenylketonuria, and cerebral organic acid disorders; NT Disorders of neurotransmission; AMN Disorders associated with hyperammonaemia; FAOD Fatty acid oxidation defects;  KETDisorders of ketogenesis or ketolysis; OA Organic acidaemias, including disorders of branched chain amino acid catabolism, 3-methylglutaconic acidurias; VIT Folate and cobalamin defects, also riboflavin transport defects, and biotin-responsive disorders; CHO Disorders of carbohydrate metabolism; LSD Lysosomal disorders; NCL Neuronal ceroid lipofuscinoses; PERPeroxisomal biogenesis disorders and disorders of single peroxisomal enzymes

View full test details for Metabolic Disorders NGS Panel

Introduction

MPS I (Hurler Syndrome) is an autosomal recessive mucopolysaccharide storage disorder caused by a deficiency of the lysosomal enzyme a-iduronidase. This deficiency results in the accumulation of heparan and dermatan sulphates in the lysosome. MPS I is a multisystemic disorder characterised by facial dysmorphism, dysostosis multiplex, and neurological deterioration. There is a broad spectrum of disease severity, in the severe form, death usually occurs during the first or second decade. Milder forms of the disorder show less rapid progression of somatic symptoms and no neurological deterioration. The disorder is divided into 3 disease sub-types according to disease symptoms. MPS I is caused by mutations in the IDUA gene, which codes for the enzyme a-iduronidase. The gene is situated on chromosome 4 at position p16.3. A number of common or recurrent mutations exist in the Caucasian population, but in other populations, many are unique to the family and include a variety of point mutations, deletions, insertions and splice junction defects.

Referral information

This service is funded by the National Commissioning Group (NCG). Samples received from England, Northern Ireland and Scotland are charged to NCG with the majority of samples being received from The Willink Metabolic Unit. New patients are initially diagnosed by enzyme analysis; therefore patients will usually have already been referred to a relevant NCG centre before DNA analysis is requested. Funding from the NCG also covers carrier detection, by DNA analysis, for family members.

View full test details for Mucopolysaccharidosis I (Hurlers Syndrome)

Introduction

MPS II (Hunter Syndrome OMIM 309900) is an X-linked recessive mucopolysaccharide storage disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulphatase. This deficiency results in the accumulation of heparan and dermatan sulphates. MPS II is a multisystemic disorder characterised by facial dysmorphism, dysostosis multiplex and neurological deterioration. Death usually occurs during the second decade. Milder forms of the disorder show slower progression of somatic features and absence of neurological problems. The classification into mild and severe forms is somewhat artificial as the disorder exhibits a wide spectrum of clinical severity, defined by the underlying genetic mutation. The iduronate sulphatase gene (IDS) is situated on the X chromosome at Xq28 spanning 24 kb and encompassing 9 exons that encode a preproprotein of 550 amino acids.

Referral information

This service is funded by the National Commissioning Group (NCG). Samples received from England, Northern Ireland and Scotland are charged to NCG with the majority of samples being received from The Willink Metabolic Unit. New patients are initially diagnosed by enzyme analysis, therefore patients will usually have already been referred to a relevant NCG centre before DNA analysis is requested. Funding from the NCG also covers carrier detection, by DNA analysis, for family members.

View full test details for Mucopolysaccharidosis II

Introduction

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is an autosomal recessive mucopolysaccharide storage disorder caused by a deficiency of various lysosomal enzymes. MPS III encompasses a group of four lysosomal storage disorders resulting from a failure to break down the glycosaminoglycan heparan sulphate. Each of the four sub-types (A, B, C, & D) of MPS III is caused by the deficiency of a different enzyme in the degradative pathway of heparan sulphate. MPS IIIA (Sanfilippo A Syndrome OMIM 252900) is caused by a deficiency of the enzyme heparan-N-sulphatase (Sulphamidase), which results in the accumulation of heparan sulphates in the lysosome. MPS IIIA is a multisystemic disorder, clinical symptoms of which usually occur after about 2 years of apparently normal development. These symptoms include hyperactivity, aggressive behaviour, delayed speech development, sleep disturbances, coarse hair, hirsutism and diarrhoea which are then followed by progressive mental retardation around 6 to 10 years of age resulting in death usually between the second and third decade of life. Type A has been reported to be the most severe, with earlier onset and rapid progression of symptoms and shorter survival. The gene for sulphamidase or N-sulphoglucosamine sulphohydrolase ( SGSH) resides on chromosome 17q25.3 spanning 11 kb and comprising 8 exons encoding a 502 amino acid precursor protein that is processed to a 482 amino acid glycoprotein that is active as a homodimer.

Referral information

This service is funded by the National Commissioning Group (NCG). Samples received from England, Northern Ireland and Scotland are charged to NCG with the majority of samples being received from The Willink Metabolic Unit. New patients are initially diagnosed by enzyme analysis, therefore patients will usually have already been referred to a relevant NCG centre before DNA analysis is requested. Funding from the NCG also covers carrier detection, by DNA analysis, for family members.

View full test details for Mucopolysaccharidosis IIIA

Introduction

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is an autosomal recessive mucopolysaccharide storage disorder caused by a deficiency of various lysosomal enzymes. MPS III encompasses a group of four lysosomal storage disorders resulting from a failure to break down the glycosaminoglycan heparan sulphate. Each of the four sub-types (A, B, C, & D) of MPS III is caused by the deficiency of a different enzyme in the degradative pathway of heparan sulphate. MPS IIIB (Sanfilippo B Syndrome) is caused by a deficiency of the enzyme alpha-N-acetylglucosaminidase (glucosaminidase), which results in the accumulation of heparan sulphates in the lysosome. MPS IIIB is a multisystemic disorder, clinical symptoms of which usually occur after about 2 years of apparently normal development. These symptoms include hyperactivity, aggressive behaviour, delayed speech development, sleep disturbances, coarse hair, hirsutism and diarrhoea which are then followed by progressive mental retardation resulting in death usually between the second and third decade of life. The gene for glucosaminidase or alpha-N-acetylglucosaminidase (gene symbol NAGLU) resides chromosome17q21 spanning 8.3 kp and comprising 6 exons that encode a 743 amino acid precursor protein that is processed to a 720 amino acid glycoprotein.

Referral information

This service is funded by the National Commissioning Group (NCG). Samples received from England, Northern Ireland and Scotland are charged to NCG with the majority of samples being received from The Willink Metabolic Unit. New patients are initially diagnosed by enzyme analysis, therefore patients will usually have already been referred to a relevant NCG centre before DNA analysis is requested. Funding from the NCG also covers carrier detection, by DNA analysis, for family members.

View full test details for Mucopolysaccharidosis IIIB

Introduction

MPS IVA Morquio disease (OMIM 253000) is an autosomal recessively inherited mucopolysaccharide storage disorder caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulphatase (GALNS, galactose-6-sulphate sulphatase) resulting in the accumulation of keratan sulphate and chondroitin-6-sulphate mainly in the cornea and cartilage, leading to distinguishing skeletal abnormalities. MPS IVA is a multisystemic disorder with clinical symptoms covering a wide spectrum of characteristics and is distinguished from other MPS by a spondyloepiphyseal dysplasia and normal intelligence. In the classical and most severe form, symptoms begin between 1-4 years of age and include tendency to fall, coarse features, dwarfism with short trunk, osteoporosis, corneal deposits, hearing impairment, and hepatomegaly. A milder form of MPS IVA is characterized by mild bone and somatic involvement with survival to 60 years of age and normal quality of life. The gene for GALNS is located on chromosome 16q24.3 and has 14 exons. The GALNS cDNA has an open reading frame of 1566 bp which encodes a 522 amino acid protein.

Referral information

This service is funded by the National Commissioning Group (NCG). Samples received from England, Northern Ireland and Scotland are charged to NCG with the majority of samples being received from The Willink Metabolic Unit. New patients are initially diagnosed by enzyme analysis, therefore patients will usually have already been referred to a relevant NCG centre before DNA analysis is requested. Funding from the NCG also covers carrier detection, by DNA analysis, for family members.

View full test details for Mucopolysaccharidosis IVa

Introduction

Niemann-Pick Disease type C (NPC) is a rare autosomal recessive neurodegenerative disorder resulting from mutations in one of two genes (NPC1 or NPC2). It is characterised by intracellular accumulation of unesterified cholesterol and glycosphingolipids (in the brain) within the late endosomes-lysosomes. NPC is clinically heterogenous with a broad spectrum of phenotypes and the age of onset ranges from perinatal through to adulthood. Common symptoms include hepatomegaly, splenomegaly, jaundice and vertical supranuclear gaze palsy (VSGP). 95% of NPC patients will have mutations in the NPC1 gene. NPC1 codes for a 1278 amino acid transmembrane glycoprotein that regulates cholesterol transport from the late endosome-lysosomes to other intracellular compartments. 4% of NPC patients will have mutations in NPC2. NPC2  codes for a 151 amino acid soluble ubiquitiously expressed lysosomal glycoprotein involved in lysosomal sterol transport. Most cases of NPC2 present in early infancy with inflammatory lung disease, with subsequent severe neurological disease and death in early childhood. Theoretically NPC2 disease is treatable by bone marrow transplantation (BMT).

Referral information

We accept referrals for mutation scanning to confirm a clinical or biochemical diagnosis. We can also offer carrier testing to family members.

View full test details for Niemann Pick Disease Type C1 and C2