1 Inborn Errors of Metabolism

1.1 Definition and Epidemiology

Inborn errors of metabolism (IEM) comprise a large group of inherited disease, some of which are due to disordered lysosomal, peroxisomal, or mitochondrial function and only some of which might be improved following HSCT. This review will be limited to the commoner indications reported in HSCT registries and which together account for the most transplanted IEM.

1.2 Diagnosis

Timely diagnosis is imperative in IEM since in all such diseases HSCT is better at preventing disease progression than reversing established disease manifestations.

Diagnosis is made in three ways:

  • Through early recognition of disease manifestations

  • Through screening of presymptomatic individuals within a known affected kindred

  • Population screening for disease, such as in the neonatal period

1.3 Classification (See Table 90.1)

Table 90.1 Classification of inborn errors of metabolism
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1.4 Risk Factors

Patient performance score at transplant predicts transplant outcome. Patients with an adverse performance score at transplant also have an inferior long-term survival as the transplant fails in advanced disease to prevent disease progression.

1.5 Prognostic Index

Not available

1.6 First-Line Treatment (Summary)

Multimodality therapies are usual in IEM.

  • Residual disease manifestations will require management beyond the HSCT episode. This will include orthopedics, ENT, and speech therapies in lysosomal storage disorders (LSDs), as well as family and educational support in all.

  • Pharmacological enzyme replacement therapy (ERT) is used in MPSI but does not correct neurological disease as it does not cross the blood-brain barrier, and alloantibody formation might limit its utility in somatic disease. It is used to improve pre-HSCT performance, but it has not been shown to influence transplant outcomes.

1.7 Second-Line Treatment (Summary)

See Sect. 90.1.6., above.

1.8 Autologous HSCT

Gene-modified auto-HSCT approaches have been shown to improve outcomes in late infantile MLD as the graft delivers more enzyme than possible in a conventional HSCT. Similar approaches have been successful in X-ALD and are likely to be a significant part of the future of HSCT in IEM.

1.9 Allogeneic HSCT in MPSIH (Hurler), MLD, and X-ALD (See Table 90.2)

Table 90.2 Main characteristics of allo-HSCT for MPSIH (Hurler), MLD, and X-ALD
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2 Osteopetrosis

2.1 Definition and Epidemiology

Osteopetrosis (OP) is a generic name of a number of rare single gene diseases characterized by sclerosis of the skeleton. At least nine forms are known with different modes of inheritance and severity, which cumulatively have an incidence ~1:100,000. The disease originates from reduced or complete lack of osteoclast function and, as a consequence, impairment of bone resorption

2.2 Diagnosis

In addition to the obligate increased bone density of all bones (X-ray), a combination of symptoms can be found in classical infantile osteopetrosis after birth. These symptoms include characteristic changes of the head (macrocephalus, frontal bossing, choanal stenosis), vision impairment (due to narrowed foramina), hematological insufficiency (thrombocytopenia, anemia, leukocytosis), hepatosplenomegaly (due to extramedullar hematopoiesis), and hypocalcemia (with secondary hyperparathyroidism). Cave: OP is a genetical and phenotypical heterogenous disease with atypical presentations (incomplete and/or delayed onset of symptoms). In these cases, an intensive work-up including spine biopsy and cranial MRI is recommended.

2.3 Classification

Osteopetrosis

Infantile “malignant” autosomal recessive OP (ARO)

Clinical symptoms in infancy, death without HSCT usually in the first decade of life, biallelic mutations in TCIRG1, CLCN7, SNX10, TNFRSF11A/ RANK, and FERMT3/KINDLIN-3; HSCT indicated, if excluded:

– “Neurodegenerative OP” (all OSTM1 and about half of CLCN7 cases)

– “Extrinsic osteoclast defects” (TNFSF11/RANKL cases)

Intermediate osteopetrosis

Clinical symptoms in the first decade, HSCT may be indicated in severe forms with hematological insufficiency and (imminent) visual impairment

Specific from: CA2 deficiency (renal tubular acidosis with cerebral calcifications): HSCT is rarely indicated

Benign osteopetrosis (ADO)

M. Albers Schoenberg (monoallelic CLCN7 mutations): HSCT not indicated

2.4 Risk Factors

There is an increased risk of pulmonary hypertension (pre and post HSCT) and SOS/VOD (post BMT). The risk of non-engraftment and rejection increases with severity of disease and age.

2.5 Prognostic Index

Not available

2.6 First-Line Treatment (Summary)

Symptomatic, steroids may be beneficial to improve hematological symptoms

2.7 Second-Line Treatment (Summary)

Not available

2.8 Autologous HSCT

Preclinical trials for gene-modified auto-HSCT for TCIRG1 defects in preparation.

2.9 Allogeneic HSCT (See Table 90.3)

Table 90.3 Main characteristics of allo-HSCT for osteopetrosis
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