2.2 Hypophosphatasia
Hypophosphatasia is caused by low activity of the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP) caused by a mutation in the
ALPL gene. The enzyme normally degrades extracellular inorganic pyrophosphate (PPi) into Pi (inorganic phosphate). Defects in this metabolic pathway leads to accumulation of PPi in the extracellular bone matrix and low alkaline phosphatase levels. [
3] Other substrates of TNSALP are pyridoxal-5-phosphate (PLP), and phosphoethanolamine (PEA). PLP is the biologically active form of vitamin B6 and high levels, as seen in hypophosphatasia, are believed to be involved in neurotoxicity. The pathophysiology of the disorder is complex: increased PPi levels inhibit normal mineralization resulting in rickets and osteomalacia, but other tissues and organs can be affected as well. For example, muscle hypotonia is a well-known feature of the disease [
4]. The disorder is extremely variable, ranging from severe infantile phenotypes to almost asymptomatic adult cases, with only dental problems. Most common skeletal symptoms are those of rickets, with bone pain, fractures and bowing of legs. The muscle hypotonia may add to walking problems. In the most severe perinatal cases, hypotonia and respiratory distress can lead to early death. Children can develop craniosynostosis and frequently have retarded growth. In adults, normal height can be achieved, but patients may suffer from skeletal complications such as fragility fractures and chronic pain [
5]. Treatment of hypophosphatasia consists of supportive care, including regular periodontal and dental care to avoid inflammation, sufficient physical activity and orthopedic interventions. In adult patients, several other modalities have been tried, including the use of teriparatide (parathyroid hormone amino acid 1–34) which has been shown to improve fracture healing and resolve stress fractures [
6].
Recently, subcutaneous asfotase alfa (Strensiq(®)), a first-in-class bone-targeted human recombinant TNSALP replacement therapy, is approved in the EU for long-term therapy in patients with pediatric-onset hypophosphatasia. It was shown that asfotase alfa in this patient group can improve rickets as evidenced by an improvement in radiographically-assessed severity scores at 24 weeks [
7]. Furthermore, patients experienced improvements in respiratory function, gross motor function, fine motor function, growth and quality of life [
8]. In life-threatening perinatal and infantile hypophosphatasia, asfotase alfa also improved overall survival [
9]. However, not all infantile cases have a favorable outcome [
10]. Knowledge on long term effectiveness is still scarce and prognostic factors to determine eligibility for treatment insufficiently known. In view of the high costs of this therapy, collaborative efforts are needed to support the decision making whom to treat. This will also become a challenge for the adult patient group, for whom this modality is still under study.
2.3 Hereditary hypophosphatemic rickets
The most common of the hereditary hypophosphatemic rickets is the X-linked form caused by a mutation in the
PHEX gene, encoding a phosphate-regulating endopeptidase homolog. Disruption of this enzyme results in a rise in FGF23 levels, suppressing transcription of sodium–phosphate co-transporters in the kidney eventually leading to renal phosphate wasting and hypophosphatemia [
11]. An autosomal dominant form resulting from gain of function mutations in FGF23 gives rise to a similar phenotype. Elevated FGF23 levels decrease synthesis and increase catabolism of active vitamin D, resulting in low levels. Patients typically have short stature and lower extremity deformities secondary to rickets at an early age, but milder forms exist. Female carriers of the X-linked variant in particular may present late, sometimes with nonspecific bone pain, fatigue, and weakness. At a later age they may have more localized complaints relating to enthesopathy and early arthropathy. Hypophosphatemia is an important diagnostic finding.
An early diagnosis is important to improve growth and prevent complications [
12]. Children should be treated with the active form of vitamin D (calcitriol or alfacalcidol) and phosphate [
12,
13]. Not all patients tolerate liquid phosphate very well and thus compliance may be a challenge. For older patients, phosphate tablets may be an alternative. Additional treatment with growth hormone has been tried in children, with inconsistent results and potential side effects. A recent trial suggests that some improvement in pre-pubertal short children can be achieved [
14]. Treatment of adults is debated: once adult height has been achieved, the indications for therapy are to reduce osteomalacia and related pain symptoms. It may be difficult in clinical practice to distinguish pain symptoms from related irreversible skeletal complications such as arthropathy. When there is biochemical evidence of osteomalacia or insufficiency fractures, treatment may be of use. In all cases, treatment should be monitored carefully to prevent complications and avoid nephrocalcinosis. For further review of treatment options, please refer to the excellent review article: A clinician’s guide to X-linked hypophosphatemia [
13]. A new treatment for both XLH and tumor-induced osteomalacia with high FGF23 levels is the administration of an Anti-FGF23 Antibody (Burosumab, Crysvita®, Ultragenyx). Recent results from a phase 2 and phase 3 studies have shown that burosumab can reduce the loss of phosphate from the kidney, improve abnormally low serum phosphate concentrations and reduces the severity of rickets as shown in x-rays [
15,
16]. Treatment has recently received marketing approval in the EU for children with XLH and is being reviewed in the US for both pediatric an adult indications.
2.4 Lysosomal storage disorders
Primary involvement of the bone marrow in inborn errors of metabolism is mainly found in the sphingolipidoses, particularly in Niemann Pick diseases and Gaucher disease. In Gaucher disease, severe bone marrow infiltration with lipid-laden macrophages can occur. Gaucher disease is caused by deficient activity of the lysosomal enzyme β-glucocerebrosidase (GBA; EC 3.2.1.45). GBA hydrolyzes the natural glycosphingolipid glucocerebroside (or glucosylceramide; GC) into glucose and ceramide. Storage of GC in macrophages gives rise to hepatosplenomegaly and involvement of the bone marrow. Severe skeletal pathology can occur in this disorder when left untreated [
17]. The pathophysiology involves mass effect of storage with cortical thinning, necrosis, fibrosis and probably low-grade inflammation. Osteopenia or osteoporosis is frequent. Timely intervention with intravenous enzyme replacement therapy or oral substrate inhibitors can prevent skeletal complications. Frequently, bone marrow examination is the clue to a diagnosis of Gaucher disease, since most patients present with splenomegalie and cytopenia, mimicking lymphoma or leukemia. Also in Niemann Pick disease, caused by acid sphingomyelinase deficiency (types A and B), skeletal features can be present as a consequence of storage cells in the marrow. This disorder mainly presents with hepatosplenomegaly and interstitial lung disease, and, in severe cases with neurological symptoms [
18]. Bone marrow involvement is less prominent than observed in Gaucher disease. Other skeletal manifestations of the disease include joint and bone pain, decreased bone mineral density and osteoporosis with a risk of fragility fractures [
19]. In young adults, short stature and delayed onset of puberty may occur, but most patients eventually attain a normal adult height [
20]. Of note, so called “pseudo-Gaucher cells” can be found in a number of disorders and should not be mistaken for the disorders mentioned above: proper diagnostic tests should be employed including genetic and enzymatic tests to confirm any disorder presenting with marrow storage cells.
2.5 The mucopolysaccharidoses and mucolipidoses
Skeletal abnormalities are the hallmark of lysosomal storage disorders caused by accumulation of glycosaminoglycans. There are eleven types of mucopolysaccharidosis (MPS; type I, II, III (with subtypes A,B,C and D), IV (subtypes A en B), VI, VII and IX), each caused by deficiency of one of 11 different GAG degrading enzymes [
21,
22]. These are multi-systemic disorders, with a wide range in presence and severity of the different clinical features. Skeletal involvement however, is universal in these disorders (with the exception of MPS III) and is of very early onset. Radiological studies in young children with MPS I, II and VI show abnormal bone development [
23] and a histological study of a MPS IV foetus show prenatal accumulation of GAGs in chondrocytes [
24].
Virtually all bones can be affected in MPS, but alterations in the shape of the skull, the bones of hips, hands, feet and spinal column are most prominent [
23]. The term most commonly used for the combination of developmental skeletal alterations in MPS is dysostosis multiplex. Length growth in MPS is reduced and the spinal abnormalities and hip dysplasia results in altered posture. Range of motion of the spine, hips, knees, shoulders, ankle and often also the elbows is reduced to variable degree in all MPS types [
25,
26] apart from type IVA, where there is joint laxity, often associated with (sub) luxation of joints [
27]. During life, the use of these abnormally shaped joint bones leads to progressive joint damage and secondary arthritic changes, limiting mobility [
28,
29]. Hip surgery and later on hip replacement are often performed in order to limit pain and to try to maintain walking ability [
28,
29]. Skeletal Pain is a frequent compliant in MPS patients [
30]. Other complications of skeletal disease in the MPSes are restrictive pulmonary disease due to altered thorax shape and thoracic wall stiffness and myelum compression resulting from spinal abnormalities.
How GAG accumulation leads to abnormal skeletal development and the occurrence of (secondary) osteoarthritis is only partially understood. In the growing skeleton, the accumulation of GAGs affects growth plate functioning, as can be seen from the disturbed growth plate architecture in MPS mouse models and a limited number of human bone specimens [
31]. Joint inflammation is apparent in MPS hips and knees and is most likely due to secondary to damage from movement of abnormally developed and maligned joints and a direct effect of increasing GAG accumulation, potentially mediated through activation of the Toll Like Receptor 4 [
32,
33].
Mucolipidosis type II and III α/β or γ are disorders caused by deficiency of the enzyme UDP-N-acetyl glucosamine-1-phosphotransferase (GLcNAc-PTase), which is involved in phosphorylation of lysosomal enzymes, ensuring correct targeting to the lysosome. Aberrant targeting of these degradation enzymes results in lysosomal accumulation of their substrates, including glycosaminoglycans and (glyco)sphingolipids. Mucolipidosis type II is the most severe form, in which rapidly progressive airway, cardiac, skeletal and nervous system disease results in death in early childhood. Mucolipidosis type III has a broader phenotypic range, with milder affected patients surviving into adulthood and displaying primarily debilitating skeletal symptoms. Skeletal symptoms in mucolipidosis bear great similarities to those of mucopolysaccharidosis, with dysostosis multiplex, secondary osteoarthritis of the joints and complications such as myelum compression and severe arthrosis of (amongst others) the hip joints, requiring surgical interventions at an early age [
28].
Treatment in the form of enzyme replacement therapy (ERT) is available for MPS type I, II, IV, VI. There may be some positive effect of ERT on joint mobility (specifically range of motion of the shoulder and hips) but by and large this effect is limited and even early treated patients go on to develop severe skeletal complications [
34,
35]. Hematological stem cell transplantation, performed in MPS I to halt neurodegeneration, does not have a significant effect on the occurrence of skeletal symptoms either [
36]. A small, short duration trial with an anti-inflammatory drug, pentosan polysulphate in MPS I suggests a positive effect on pain [
37]. There are no disease specific therapies for mucolipidosis type II and III. In all these disorders supportive care is of great importance, focusing on pain management, physiotherapy and well timed surgical interventions executed by a team experienced in treating these complex multisystem disorders.
2.6 Mannosidoses
Alpha mannosidosis is a lysosomal storage disorder in which deficiency of the enzyme α-mannosidase leads to accumulation of mannose-rich oligosaccharides. Similar to the mucopolysaccharidoses and mucolipidoses, this is a clinically widely variable multisystemic disorder with neurocognitive and psychiatric symptoms, corneal clouding or cataract, hearing loss, immune deficiencies, myopathy and skeletal abnormalities. Dysostosis multiplex with skull abnormalities, kyphoscoliosis, pectus carinatum, hip dysplasia and hand and feet deformities are present in variable degree in the majority of patients [
38,
39]. Secondary osteoarthritis of the large joints can occur [
40] and an increasing incidence of arthrosis is found as patients get older [
41]. Alpha mannosidosis has been treated with hematopoeitic stem cell transplantation [
42,
43], but there are not enough data to evaluate the effect on the musculoskeletal symptoms of the disorder. Enzyme replacement therapy has been recently granted marketing authorization under exceptional circumstances in the EU. Long term the data on the effectiveness of this treatment, including the effect on musculoskeletal symptoms, will be evaluated.
Beta mannosidosis is an extremely rare disorder caused by accumulation of complex disaccharides due to deficiency of the lysosomal beta-mannosidase enzyme, with few published cases. It has a wide clinical spectrum of which skeletal abnormalities can be a feature [
44].
2.7 Pycnodysostosis
Pycnodysostosis is an autosomal recessive metabolic bone disorder caused by mutations in the cathepsin K (CTSK) gene [
45]. Cathepsin K is a lysosomal protease which is secreted into the sealed extracellular compartment, where it is involved in degradation of bone matrix proteins (e.g. collagen type I, osteonectin and osteopontin). Deficient cathepsin K activity results fragile bones with increased mineral content. Clinically, the disorder is characterized by short stature, pathological fractures and bone dysplasia [
46,
47]. Especially craniofacial and dental abnormalities and stubby hands and feet with acroosteolysis are typical of pycnodysostosis, though the latter is not found in all patients [
47‐
49]. No specific treatment for pycnodysostosis is available. Multidisciplinary supportive care, including attention for the risk of upper airway obstruction, is indicated [
50].
2.8 Alkaptonuria
Alkaptonuria is an autosomal recessive metabolic disorder in the catabolic pathway of the amino acids phenylalanine and tyrosine. Decreased activity of the enzyme homogentisate 1,2-dioxygenase leads to accumulation of homogentisic acid (HGA) and its oxydated derivative benzoquinone acetic acid (BQA) in connective tissue, cartilage and body fluids (e.g. urine, sweat). The deposition of BQA polymer in connective tissue triggers the progressive tissue damage observed in this disorder. The disorder is sometimes recognized early in life because of discoloration of urine when exposed to oxygen or alkali, but symptomatic disease generally does not develop until the third decade of life. Back and joint pain are the first symptoms to occur and over time, progressive disease results in progressive deformation of the spine and arthrosis of the large joints, necessitating joint replacement at an early age [
51,
52]. Other complications of the disease are the formation of stones in the genitourinary tract and cardiac valve disease.
Limiting HGA production can be attempted by a protein restricted diet, though this is hard to comply with, especially in a period of life when individuals are still asymptomatic [
53]. Nitisinone (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, NTBC), inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase, can be used to reduce HGA synthesis. In a first clinical treatment trial, urinary HGA excretion was reduced by >95% in response to the highest administered daily dose (8 mg) [
54]. Safety of this treatment (NTBC increases tyrosine, with unknown long term consequences) and its effectiveness in preventing clinical complications remains to be proven and a phase 3 trial (Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2)) is currently ongoing.