83 Lipidoses

Lysosomal storage diseases (LSDs) are caused by the accumulation of proteins, polysaccharides, and lipids in the lysosomes of cells because of a genetic failure of enzymes needed for their breakdown. The progressive accumulation of substrates frequently affects the skeleton. The pathophysiology is not completely understood and likely involves a complicated interplay of substrate storage, tissue inflammation, and epigenetic factors. LSDs can be categorized as sphingolipidoses and mucolipidoses, and mucopolysaccharidoses (discussed in Chapter 84, “Mucopolysaccharidoses”). Table 83.1 summarizes the incidence and musculoskeletal findings of the sphingolipidoses and mucolipidoses, which are groups of diseases that share musculoskeletal imaging findings. Diagnosis relies primarily on peripheral blood lysosomal enzyme activity, but DNA testing is the most reliable technique for definitive diagnosis and detecting disease transmission.

Gaucher disease (GD) is an autosomal recessive disorder caused by deficient β-glucocerebrosidase activity and accumulation of the lipid glucosylceramide. Macrophages, when filled with glucosylceramide, are referred to as Gaucher cells, which have a characteristic crumpled silk appearance of the cytoplasm. GD is the most common LSD and is classically subdivided into 3 different phenotypes. Type I GD is by far the most frequent with a particularly high frequency in the Ashkenazi Jewish population (1 in 850). There is no central nervous system involvement, although Parkinson disease has been described in these patients. Type 1 GD has a highly variable presentation, even among twins, which most often involves the bone (80%), but also results in cytopenia and hepatosplenomegaly. Types 2 and 3 GD are much less frequent and have either acute (type 2) or chronic (type 3) neurologic disease. Patients with type 2 GD die in infancy, and patients with type 3 GD present in childhood with a less severe phenotype.

Bone complications can be a first symptom of disease, presenting as bone crises, which are episodes of excruciating pain, possibly necessitating hospitalization for pain management. Patients also suffer from a chronic inflammatory state that is exacerbated during these crises, which are often accompanied by localized warmth and swelling, leukocytosis, raised ESR and fever, similar in presentation to juvenile idiopathic arthritis (JIA) and RA. Up to 43% of patients have a history of ON with up to 22% undergoing joint replacement. Osteoporosis is common in patients with GD, possibly related to chronic inflammation, in a similar fashion to the osteoporosis of JIA and RA. Both longer disease duration and history of splenectomy are associated with ON and osteoporosis.

MRI is the imaging modality of choice. Sagittal T1W and STIR sequences of the lumbar spine, coronal T1W and STIR imaging of the pelvis, and coronal T1W and STIR sequences of both femora are optimal to evaluate disease status. In younger patients, T1W and STIR images of the tibias are useful, because the presence of red marrow in the femurs can make the detection of involvement difficult. Patients should have follow-up imaging every 12-24 months and/or at times of enzyme replacement therapy or substrate removal therapy (ERT and SRT, respectively). At the same sitting, axial T1W and T2W images are acquired through the upper abdomen to assess severity of spleen and liver involvement. DXA scanning is generally recommended for the evaluation and follow-up of bone density at 1-2 year intervals. The use of radiography is limited to evaluation of acute pain (eg, exclude fractures). Nuclear medicine, especially technetium 99m sestamibi (^99mTc-sestamibi), is a useful alternative in evaluating disease status in patients with GD who are unable to undergo MRI or when MRI is unavailable.

Fabry disease (FD) is an X-linked recessive disease resulting in deficient galactosidase A. Together, GD and FD account for 20% of LSDs with a combined prevalence of 1 in 38,400 (live) births. Attacks of pain (Fabry crisis) in the extremities, similar to the bone crisis of GD, begin during adulthood or adolescence, decreasing in frequency and severity with age. Like GD, the Fabry crisis may be accompanied by systemic inflammation resulting in a misdiagnosis of inflammatory arthritis (eg, JIA, RA). The mean delay in diagnosis is approximately 14 years for male patients and 16 years in female heterozygotes from symptom onset. Similar to GD, osteopenia and osteoporosis are reported in patients with FD. More specific signs of FD include skin papules (angiokeratoma) and cornea color changes (cornea verticillata) with hypohidrosis or anhidrosis. Patients also experience gastrointestinal symptoms. Renal, cardiac, and cerebrovascular complications result in major morbidity if untreated.

Although not as well-defined as for GD, a similar approach to evaluate the severity of disease involvement and response to treatment using MRI is practical. Nuclear medicine techniques are not well described for FD.

NPD is an autosomal recessive disorder caused by deficiency of acid sphingomyelinase composed of 3 subtypes (A-C). The infiltration of bone marrow and spleen by lipid-engorged cells with a soap bubble appearance results in anemia and thrombocytopenia (also seen in GD). Neurologic involvement is common.

A similar approach to evaluate the severity of musculoskeletal disease involvement and response to treatment using MRI is practical. Nuclear medicine techniques are not well described for NPD.

Mucolipidosis (ML)—ML I, ML II, ML III, ML IV—and α-mannosidosis are rare, autosomal recessive genetic disorders caused by a deficiency in enzymes that metabolize glycoproteins. ML I-III result in musculoskeletal deformities resembling mucopolysaccharidosis (MPS) I. ML IV is not associated with skeletal disease. ML II rarely presents in adults because of death during childhood. There is a similar presentation of ML and MPS patients, described in Chapter 84, “Mucopolysaccharidoses.” The treatment options are limited to treating symptoms as there are no medical treatments. These include surgery for cervical stenosis, kyphoscoliosis and hip dysplasia.

The imaging strategy mirrors that of the MPS (see Chapter 84). The spectrum of findings seen in ML and MPS called dysostosis multiplex (Table 83.2) is evaluated using a baseline skeletal survey, typically acquired during childhood. Lateral flexion and extension radiographs of the cervical spine, a scoliosis series, and an AP pelvis radiograph should be obtained until skeletal maturity to evaluate for instability, gibbus deformity, and hip dysplasia. An annual cervical spine MRI may also be valuable given the frequency of cervical stenosis and its insidious onset.