Inborn Errors of Metabolism and Osteopetrosis

  • Robert WynnEmail author
  • Ansgar Schulz
Open Access


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.

90.1 Inborn Errors of Metabolism

90.1.1 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.

90.1.2 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

90.1.3 Classification (See Table 90.1)

Table 90.1

Classification of inborn errors of metabolism


Hurler syndrome, MPSIH

Hurler syndrome. This is the most severe phenotype of iduronidase deficiency, a lysosomal storage disorder (LSD) which results in the accumulation of glycosaminoglycans. There is progressive multi-organ dysfunction including psychomotor retardation, severe skeletal disease, life-threatening cardiopulmonary complications, and premature death

HSCT prevents early death and attenuates the multi-system disease manifestations as the deficient enzyme is donated by engrafted donor leucocytes to host tissues (“cross-correction”)

X-linked adrenoleukodystrophy

In this X-linked disorder, there is accumulation of very long-chain fatty acids in the brain and adrenal glands arising from their defective metabolism by a peroxisomal, membrane protein encoded by the ABCD1 gene

Clinical manifestations in genetically affected boys are highly variable, even within a kindred. The principle role of HSCT is to prevent progression of early cerebral ALD, an inflammatory demyelinating disease of childhood that is seen in about 40% of genetically affected individuals

HSCT does not influence other illness such as adrenal insufficiency or the later myeloneuropathy of the spinal cord

Metachromatic leukodystrophy (MLD)

This is a recessive LSD, and there is accumulation of sulfatides, a myelin component, due to deficiency of the arylsulfatase A enzyme. There is demyelination in the central and peripheral nervous systems, and clinical manifestations are related to residual enzyme activity. In the late infantile disease, the commonest and most severe phenotype, there is progressive neurological dysfunction and early death usually by the age of 4 years

HSCT is ineffective in preventing progression of early presenting disease, although it may have a greater impact later, attenuated disease especially when applied early in the course of that illness

90.1.4 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.

90.1.5 Prognostic Index

Not available

90.1.6 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.

90.1.7 Second-Line Treatment (Summary)

See Sect. 90.1.6., above.

90.1.8 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.

90.1.9 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

Indicated in

MPSIH (Hurler) is a standard indication for HSCT

In MLD, HSCT is usually reserved for later (attenuated) forms of the disease, namely, juvenile and adult forms

In X-ALD, HSCT is indicated in early cerebral inflammatory disease. Ordinarily, a genetically affected individual has serial (annual) MRI scans from early childhood, and HSCT is carried out when there are early MRI changes of demyelination (the MRI changes are scored as a Loes score)


Where MPSIH is diagnosed late then the opportunity for HSCT to meaningfully alter the natural history of the disease might be lost. No hard and fast rules can be applied, but often HSCT is not offered to a child presenting beyond the age of 30 months, but careful multidisciplinary assessment is required

Late infantile MLD is not usually considered for HSCT. Note that such disease—if diagnosed in a timely fashion—has been shown to be markedly improved using an autologous, ex vivo HSC gene therapy approach

Advanced cerebral X-ALD is considered a contraindication to HSCT. Disease will progress through transplant. The MRI scan-derived Loes score might predict those that will benefit most from HSCT


In LSD, non-carrier MFD > MUD > carrier MFD

In LSD, UCB is frequently preferred to BM, since the post-HSCT chimerism is higher in scuh recipients, and the interval between referral and HSCT is likely shortest (rejection might be higher using UCB)

PB is rarely used as a donor cell source


Haplo-HSCT is rarely indicated in IEM

Conditioning: standard

Engraftment is difficult in IEM. Generally reduced intensity conditioning and ex vivo TCD are associated with high rates of graft loss

MSD/MFD: IV BU (MAC AUC)/FLU (160 mg/m2)

MUD: IV BU (MAC AUC)/FLU (160 mg/m2)

Conditioning: reduced toxicity

Occasionally reduced toxicity conditioning might be employed

In somatic IEM, such as Wolman or attenuated MPS: TREO/FLU (160 mg/m2)/TT (10 mg/kg)

Source of SC

UCB often preferred in LSD

BM rather than PB in MUD donors

No ex vivo TCD as this is shown to contribute to graft loss

GvHD prophylaxis


MUD: ATG/Campath, CSA + MMF

MUC UCB: Proximal ATG, CSA + MMF or CSA + PRD



MSD: < 5%

MUD: <10%

Engrafted survival of >80% and

overall survival of 90%

MAC AUC doses adjusted to achieve MAC AUC, MSD match sibling donor, MFD match family donor, MUD much unrelated donor, LSD lysosomal storage disorder, EIM inborn errors of metabolism

90.2 Osteopetrosis

90.2.1 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

90.2.2 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.

90.2.3 Classification


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

90.2.4 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.

90.2.5 Prognostic Index

Not available

90.2.6 First-Line Treatment (Summary)

Symptomatic, steroids may be beneficial to improve hematological symptoms

90.2.7 Second-Line Treatment (Summary)

Not available

90.2.8 Autologous HSCT

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

90.2.9 Allogeneic HSCT (See Table 90.3)

Table 90.3

Main characteristics of allo-HSCT for osteopetrosis

Indicated in

Infantile osteopetrosis: clinical symptoms and exclusion of neurodegenerative and extrinsic osteoclast defect


Neurodegenerative osteopetrosis: symptoms (non-hypocalcemic convulsions/EEC changes, severe progredient developmental delay) and/or biallelic mutations in OSTM1 and CLCN7; cave: only about half of CLCN7 mutations cause neurodegeneration

Osteopetrosis not intrinsic to defects in differentiation or function in osteoclasts: TNFSF11/RANKL


MFD > MUD > haplo (cord blood not recommended)

Conditioning: standard

MSD/MFD: IV BU (MAC AUC)/FLU (160 mg/m2)

MUD: IV BU (MAC AUC)/FLU (160 mg/m2)/TT (10 mg/kg)

Haplo: IV BU (MAC AUC)/FLU (160 mg/m2)/TT (15 mg/kg)

Conditioning: reduced toxicity

MSD/MFD: TREO/FLU (160 mg/m2)/TT (10 mg/kg)

MUD: TREO/FLU (160 mg/m2)/TT (10 mg/kg)

Conditioning: post Cy protocol

In patients >10 months of age and haplo donors, an adapted PT-CY protocol should be considered (see updated EBMT guidelines)

Source of SC

Matched donors, PT-CY protocol: T replete BM > PB

Haplo (standard protocol): TCD PB

GvHD prophylaxis

MSD/MFD: CSA + MMF (consider ATG or Campath in MFD)

MUD: CSA + MMF + ATG (or Campath)

Haplo—TCD: ATG (or Campath), consider MMF

Haplo—T replete: Campath, PT-CY, TAC (or CSA) + MMF


MSD/MUD: 10–20%

Haplo: ~30 to 40%; cave: high rejection rate (>50%) in pts > 10 months


MSD: ~90%

MUD: ~80%

Haplo/MMUD: 60–70%

MAC AUC doses adjusted to achieve MAC AUC, MSD match sibling donor, MFD match family donor, MUD much unrelated donor, MMUD mismatch unrelated donor

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Authors and Affiliations

  1. 1.Blood and Marrow Transplant UnitRoyal Manchester Children’s Hospital, University of ManchesterManchesterUK
  2. 2.Department of PediatricsUniversity Medical Center UlmUlmGermany

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