1 Inborn Errors of Metabolism

1.1 Definition and Epidemiology

Inborn errors of metabolism (IEM) comprise a large group of inherited diseases. They are individually rare. HCT is indicated only in a small number of diseases.

It can be curative in certain lysosomal disorders, peroxisomal disorders or certain disorders of mitochondrial function. This review will be limited to the commoner indications reported in HCT registries and which together account for most of transplanted IEM.

1.2 Diagnosis

Timely diagnosis is imperative in IEM since in all such diseases, HCT is better at preventing disease progression than reversing established disease manifestations. Indeed, HCT might be contraindicated in those patients presenting with more advanced disease.

This is true for all lysosomal storage diseases and for X-ALD.

Diagnosis is made in three ways

  • Through early clinical recognition of disease manifestations

  • Through screening of pre-symptomatic individuals within a known affected kindred

  • Population screening for disease, such as in the neonatal period, with new-born screening

In X-ALD, transplant is indicated for the prevention of progression of cerebral inflammation, which manifests with a high interpersonal variability, even within an affected kindred. Progress of inflammation is detected with serial cerebral MRI scans (at 6 or 12 monthly intervals) in boys, that are genetically affected but currently well.

1.3 Classification (See Table 91.1)

Table 91.1 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 HCT episode. This will include orthopaedics, ENT, and speech therapy in lysosomal storage disorders (LSDs), as well as family and educational support.

  • 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 use in somatic disease. It is used to improve pre-HCT performance, but it has not been shown to influence transplant outcomes.

1.7 Second-Line Treatment (Summary)

See Sect. 91.1.6., above.

1.8 Autologous HCT

Gene-modified auto-HCT approaches have been shown to improve outcomes in late infantile MLD as the graft delivers more enzyme than possible in a conventional HCT. This treatment has been recently licensed by the EMA for therapy in several European countries.

Similar approaches are under investigation for other lysosomal disorders including MPSIIIA, MPSII, Gaucher (particularly where there is neurological involvement, GD3), and MPSIH. It is likely that this approach will greatly change the landscape of therapeutic approaches in metabolic disease in the coming years.

Similar approaches have been successful in X-ALD. The mechanism of action is different, since there is no supraphysiological production of enzyme. Of course, autologous HCT is also safer. Consecutively, no immune suppression is needed with a lower risk of infections and no risk of GVHD.

1.9 Allogeneic HCT in MPSIH (Hurler), MLD, and X-ALD (See Table 91.2)

Table 91.2 Main characteristics of allo-HCT for MPSIH (Hurler), MLD, and X-ALD
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2 Osteopetrosis

2.1 Definition and Epidemiology

Osteopetrosis (OP) is a generic name for a variety of rare monogenetic diseases characterized by sclerosis of the skeleton. At least nine variants 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 HCT usually in the first decade of life, biallelic mutations in TCIRG1, CLCN7, SNX10, TNFRSF11A/RANK, and FERMT3/KINDLIN-3; HCT 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, HCT may be indicated in severe forms with hematological insufficiency and (imminent) visual impairment after individual assessment

Specific from: CA2 deficiency (renal tubular acidosis with cerebral calcifications): HCT may be considered after individual assessment in cases with hematological insufficiency and (imminent) visual impairment if neurological and renal problems are controlled

Benign osteopetrosis (ADO)

M. Albers Schoenberg (monoallelic CLCN7 mutations): HCT usually not indicated; HCT may be considered after individual assessment in clinical severe cases

2.4 Risk Factors

There is an increased risk of pulmonary hypertension (pre and post HCT) 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 HCT

Clinical trials for gene-modified auto-HCT for TCIRG1 defects in preparation.

2.9 Allogeneic HCT (See Table 91.3)

Table 91.3 Main characteristics of allo-HCT for osteopetrosis
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