Louise Simmons Clinical Nurse Specialist Inherited Metabolic Disorders (IMD) Birmingham Children s Hospital

Louise Simmons Clinical Nurse Specialist Inherited Metabolic Disorders (IMD) Birmingham Children s Hospital

Individually rare Collectively not uncommon - 1:700 - Childhood cancer 1:500 Genetically inherited AR, X-linked, AD, Mitochondrial

Disorders of amino acid metabolism Disorders of energy metabolism Organelle diseases Mitochondrial Lysosomal Peroxisomal Others Disorders of neurotransmitter metabolism Disorders of glycosylation Disorders of sterol synthesis Disorders of purine & pyrimidine metabolism

Lipids Glycogen Food Glycogenolysis I: Proximal defects - treatable Fatty acid oxidation Gluconeogenesis Pyruvate AcetylCoA LACTATE Pyruvate dehydrogenase complex Glucose II: Distal defects - untreatable Kreb s cycle NADH2, FADH2 Respiratory chain ATP Figure: Overview of energy metabolism

Mitochondrial respiratory chain defects Pyruvate dehydrogenase deficiency (PDH) Pyruvate carboxylase deficiency Kreb s cycle defects Mitochondrial depletion syndrome

Lactic acidosis Developmental delay, regression, hypotonia, seizures, strokes Variable clinical presentation Age at presentation very variable Progressive

Several apparently unrelated systems may be affected Neurological disease Cardiac disease Renal Liver Myopathy Ophthalmologic disease Haematological Deafness Endocrine, diabetes Lactic Acidosis

Some combinations can constitute recognisable syndromes e.g. MELAS, MERFF, Leigh s, NARP, Alpers, Barths, Pearsons Overlap between syndromes

Symptomatic management - physiotherapy - OT - treatment of seizures, dystonia, spasticity - feeding support - respiratory, cardiac, renal, other support Palliative care Mitochondrial Cocktail Prenatal diagnosis

Peroxisomal disorders Lysosomal disorders Disorders of glycosylation (CDG syndrome) Transport disorders e.g. Wilson and Menkes disease

Dysmorphism Brain involvement neuroregression Spectrum of severity Most are untreatable symptomatic management Newer specific treatments may be available - enzyme replacement, gene therapy, HSCT

Recycling centres of the cell

DISORDER DEFICIENT ENZYME ACCUMULATING GAGs MPS I Iduronidase DS, HS MPS II Iduronate sulfatase DS, HS MPS III Sulfamidase, Glucosamine-6- HS sulfatase, N-acetylglucoasaminidase, N-acetyltransferase MPS IV Galactose-6-sulfatase, - KS galactosidase MPS VI N-acetylglucosamine-4- DS sulfatase MPS VII -glucuronidase HS, DS, CS

Types I-VII based on pattern of GAG excretion Main primary molecules that accumulate are Heparan sulfate, Dermatan sulfate, Chondroitin sulfate, Keratan sulfate Broad correlation with primary storage molecule - HS neurological involvement - DS, KS somatic & skeletal involvement

Most Severe Attenuated Developmental delay Little or no intellectual defect Normal intelligence More progressive disease Less progressive disease Death in first decade Death in teens and 20 s normal life span

Presentation in 1 st year of life with developmental delay Dysmorphism Skeletal deformities, stiff joints Hepatosplenomegaly, herniae Cardiac involvement Corneal clouding Regression, death by 5-8 years

~1:130,000 Similar to MPS I but Behavioural problems Absent corneal clouding Skin papules Less rapid progression death in early teens X-linked

~1:50,000 A, B, C D: All types have similar features Dysmorphism not prominent early on Behavioural & sleep problems invariably present usual presenting feature Milder dysostosis, systemic involvement 3 clinical phases - <4 years, 4-10 years, >10y

~1:170,000 Intellectual preservation Severe skeletal involvement Very short - <100cm No facial dysmorphism Joint laxity instead of stiffness Cardiac, corneal involvement similar to other MPS..

Variation in severity Severe psychological issues Progressive cervical spinal involvement results in loss of mobility by late childhood - Can cause sudden death Survival to early adulthood.

~1:250,000 Variable age at presentation Similar to MPS I but preserved intellect even in severe form Cervical spinal problems more prominent Significant respiratory problems

Non immune hydrops fetalis lysosomal disorders in extremis MPS II, IV, VII ISSD Gaucher Niemann Pick C Sialidosis Galactosialidosis GM1 gangliosidosis I-cell disease Other IMDs.

Disorders of degradation of glycan portions of glycoproteins Primary accumulation of oligosaccharides, glycopeptides and glycolipids Noteworthy for prominent CNS involvement - Mannosidosis, Sialidoses, Infantile Sialic Acid Storage Disease, Fucosidosis.

Galactosialidosis Mucolipidosis II & III Multiple sulfatase deficiency

Leukodystrophy Storage in oligodendrocytes and Schwann cells Damage to myelin-producing cells (white matter disease) Neurological regression, spasticity, peripheral neuropathy, seizures Peroxisomal Disorders - Zellewegers Syndrome, ALD Lysosomal Storage Disorders Sphingolipidoses: metachromatic leukodystrophy, Krabbe's disease,

Variable phenotype and age of presentation. Dysmorphism, neuroregression, seizures, organomegaly. GM2 gangliosidosis Tay Sachs & Sandhoffs Infantile onset with neuroregression, hyperacusis, cherry red spot, seizures Milder phenotypes have been described

Completely different conditions! NPA/B Single enzyme deficiency NPA very severe disorder and severly life-limiting NPB variable due to no neurological involvement NPC Cholesterol trafficking defect. Splenomegaly, neonatal jaundice, neurodevelopmental regression in SOME cases at SOME point in life! Cataplexy common New treatments being developed

Clinical heterogeneity Potential for treatment in many conditions - ERT for MPS I, II, IV, VI, Pompe - Bone marrow transplantation for MPS I, others - symptomatic management Newer treatments under development and in clinical trial stages. Prenatal diagnosis possible for all

Aicardi Goutiere Syndrome (AGS) PLAN / INAD (PLA2G6) Cockaynes (DNA reapair defects) Severe Smith Lemli-Opitz (SLO) Non-ketotic Hyperglycinaemia (NKH) Hypomyelination Diseases (Pelizaeus-merzbacher disease) Vanishing White Matter Disease Canavan s Disease

IMDs are individually rare but collectively common Broad range of presentation Specific treatments available for some conditions Symptomatic treatment mainstay of treatment for others

Family Support Breaking bad news and diagnoses Referrals for appropriate services, including specialist advice and experiences to help focus and inform Complex & difficult symptomatic management often in conjuction with local services Home Visits (often joint with local teams) Advanced care planning

Any questions? Any cases / patients for discussion?