Unexplained metabolic phenotype
Conditions
Interventions
None
Sponsors
UMD
Eligibility
Inclusion criteria
Inclusion criteria: Patients with an unexplained metabolic phenotype defined as: neurological symptoms and/or abnormalities on (physical) examination suggestive of an inborn error of metabolism (energy deficiency, intoxication type or storage type): Energy deficiency: neurological (repeated rhabdomyolysis, verified exercise intolerance, neuropathy, myopathy, ataxia), ophthalmological (retinitis pigmentosa (RP)), otological (hearing loss, deafness), endocrine (hypoparathyroidism, hypoglycemia) Intoxication: neurological (encephalopathy, regression, movement disorder, psychiatric symptoms), ophthalmological (lens luxation), organic (liver and kidney function abnormalities) Storage: neurological (regression, psychiatric symptoms), ophthalmological (cataract/corneal clouding), skin (angiokeratomas), blood (cytopenias), organic (hepatosplenomegaly, cardiac hypertrophy, skeletal abnormalities, short stature, coarse facial features, umbilical/inguinal hernia) AND / OR one or more of the following suggesting a deficient metabolic pathway or process: • abnormal metabolites in body fluids (CSF, urine, blood) • functional studies at a biochemical/cellular level indicative of a metabolic deficiency (e.g. respiratory chain complex analysis) • organ dysfunction (e.g. liver or kidney failure) • an abnormal clinical function test (protein loading test, fasting test, meal test, validated exercise test, non-ischaemic underarm test) • abnormalities on imaging (neuro-imaging (including spectroscopy); X-rays (dysostoses or other bone abnormalities); ultrasound (enlarged liver/spleen)) • a VUS (variant of unknown significance) in a gene involved in metabolism AND no diagnosis despite extensive clinical, metabolic and genetic investigations • SNP-array/array-CGH: inconclusive results • metabolic screening according to up to date clinical protocols: inconclusive results • WES (open or gene panel): no class 4 or 5 variants in a known (OMIM annotated) disease related gene that can fully explain the phenotype of the patient
Exclusion criteria
Exclusion criteria: A patient will be excluded from participation in this study if: • after discussion by the ZOEMBA team (see Methods) he/she is suspected to have: - a genetic condition for which there is a simpler and more cost-effective test available for diagnosis - a complex genetic disorder (caused by a combination of multiple genes and/or environmental influences) - a condition that is thought to be caused by factors that are non-genetic, such as infection, injury or toxic exposure • he/she is unable to follow the study protocol (e.g. additional blood samples)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1) identification of a genetic variant and alignment with its biochemical and phenotypical abnormalities | — |
Secondary
| Measure | Time frame |
|---|---|
| 2) evaluating the diagnostic yield of combined WES/WGS and omics techniques | — |
Contacts
Public ContactElise Termeulen
Amsterdam UMC / United for metabolic diseases (UMD)
Outcome results
None listed