Table 2. Basic defects, and clinical and respiratory features of selected inherited metabolic diseases
Disorder and subtypeBasic defectGeneClinical featuresRespiratory manifestations
Niemann–Pick disease
    Type AAcid sphingomyelinase deficiencySMPD1Onset in infancy, retinopathy hepatosplenomegaly and rapidly progressive neurological deteriorationRecurrent bronchitis or aspiration pneumonia culminating in life-threatening or fatal events
    Type BAcid sphingomyelinase deficiencySMPD1Onset in childhood, hepatosplenomegaly, growth retardation and mild clinical courseMild dyspnoea on exertion, interstitial lung disease, and severe and fatal respiratory insufficiency
    Type CAbnormal trafficking of sphingolipidsNPC1 and NPC2Variable age at onset, hepatosplenomegaly, progressive neurological involvement and subacute clinical courseInterstitial lung disease, aspiration pneumonia, and pulmonary alveolar proteinosis with respiratory insufficiency (in NPC2 genotype)
Gaucher disease
    Type 1β-glucocerebrosidase deficiencyGBA (high prevalence of the N370S mutation)Non-neuronopathic form, hepatosplenomegaly, thrombocytopenia, and bone diseaseVentilatory dysfunction, recurrent respiratory infections and pulmonary hypertension
    Type 2β-glucocerebrosidase deficiencyGBA (high prevalence of L444P/L444P and other “neuronopathic” mutations)Acute neurological form, early onset, rapidly progressing brainstem dysfunction and hepatosplenomegalyVentilatory dysfunction, aspiration pneumonia, and increased risk of interstitial lung disease in homozygotes for L444P mutation
    Type 3β-glucocerebrosidase deficiencyGBA (high prevalence of L444P/L444P mutation)Subacute progressive encephalopathy (oculomotor apraxia, epilepsy and ataxia) and systemic manifestations as in type 1Ventilatory dysfunction, aspiration pneumonia, and increased risk of interstitial lung disease in homozygotes for L444P mutation
Fabry diseaseα-galactosidase AGLARenal and cardiac insufficiency, neuropathic pain, angiokeratoma and premature strokeWheezing, chronic bronchitis and exercise intolerance
Farber lipogranulomatosisAcid ceramidaseASAH1Joint swelling, subcutaneous nodules and delayed psychomotor developmentAphonia, lower airways infections and fatal respiratory failure
Hermansky–Pudlak syndromeDisrupted biogenesis of lysosome-related organellesHPS1Oculocutaneous albinism, bleeding, diathesis, neutropenia and granulomatous colitisPulmonary fibrosis and interstitial lung disease
Wolman diseaseDeficient activity of lysosomal acid lipaseLIPAHepatosplenomegaly, gastrointestinal symptoms and calcified adrenal glandsPulmonary hypertension
Lysinuric protein intoleranceDefective cationic amino acid transportSLC7A7Failure to thrive, osteoporosis, bone marrow anomalies, hepatosplenomegaly, hyperammonaemia, kidney disease and gastrointestinal symptomsWheezing, respiratory infections, exercise intolerance, haemoptysis, interstitial lung disease, and pulmonary alveolar proteinosis
    Type IaGlucose-6 phosphataseG6PCHepatomegaly, growth retardation, osteopenia, full-cheeked round face, nephromegaly and platelet dysfunctionPulmonary hypertension
    Type IbGlucose-6 phosphate translocaseSLC37A4As type Ia, neutropenia and neutrophil dysfunctionPulmonary hypertension
    Type IIα-glucosidaseGAAInfantile onset: hepatomegaly, feeding difficulties, cardiomegaly and muscle weakness Juvenile and adult-onset: muscle weakness and no cardiac diseaseAlveolar hypoventilation and risk of respiratory failure
MucopolysaccharidosesLysosomal enzymes in the glycosamino-glycan breakdown pathwayI: IDUA; II: IDS; IIIA: SGSH; IIIB: NAGLU; IIIC: HGSNAT; IIID: GNS; IVA: GALNS; IVB: GLB1; VI: ARSB; VII: GUSB; IX: HYAL1Facial dysmorphisms, macrocephaly, dysostosis, joint motion limitation, hepatosplenomegaly, cardiac valve thickening, cardiomegaly and mental retardation (not in all types)Type I, II, IV and VI: recurrent upper airway infections, obstructive sleep apnoea syndrome and severe respiratory failure