Sphingomyelinase Deficiency Clinical Presentation

Updated: May 29, 2020
  • Author: Jaimin M Patel, MD, MBBS, MS; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Presentation

History

Niemann-Pick disease (NPD) type A

The clinical presentation and course of NPD type A is relatively uniform and is characterized by normal appearance at birth. Some patients may have neonatal edema, and hydrops fetalis may occur. The first sign detected is usually the presence of hepatosplenomegaly, which is evident at age 3 months and becomes progressively greater. The liver is usually enlarged out of proportion to the spleen.

The patient's development seems to progress normally until about age 6 months, followed by a plateau phase from 6 months until about age 15 months. Lastly, rapidly progressive psychomotor and intellectual deterioration occur. Psychomotor development does not progress beyond the 12-month level, and in later stages, the affected child is completely unable to interact with the environment.

Mild hypotonia may be evident by age 6 months, followed by progressive loss of tone and deep tendon reflexes. With disease progression, loss of motor function occurs, and in the final stages, spasticity and rigidity are evident.

Affected infants exhibit feeding problems, failure to thrive, recurrent respiratory tract infections, and irritability. Most children with NPD type A die before age 2-3 years, often from respiratory failure following pulmonary infection.

Atypical presentations of NPD type A have been reported, including unilateral tremors and ipsilateral hemiparesis, with regression of milestones, followed by the development of hepatosplenomegaly. [13]

NPD type B

The clinical presentation and course in patients with NPD type B disease is milder and more variable. The condition is diagnosed in most patients in infancy or childhood when enlargement of the liver, spleen, or both is detected during routine physical examination.

At diagnosis, patients with NPD type B also have evidence of mild pulmonary involvement, usually detected as a diffuse reticular or finely nodular infiltration on chest radiograph films.

In many patients, hepatosplenomegaly is particularly prominent in childhood; however, with increasing linear growth, the abdominal protuberance decreases and becomes less conspicuous.

In mildly affected patients, splenomegaly may not be noted until adulthood, and disease manifestations may be minimal.

In most patients with NPD type B, decreased pulmonary diffusion caused by storage of sphingomyelin in pulmonary macrophages becomes evident in childhood and progresses with age. Severely affected individuals may experience significant pulmonary compromise by age 15-20 years. Such patients have low PO2 values and dyspnea on exertion.

Recurrent pneumonia and life-threatening bronchopneumonias may occur, and cor pulmonale has been described. Severely affected patients may also have liver involvement leading to life-threatening cirrhosis, portal hypertension, and ascites.

Clinically significant pancytopenia caused by secondary hypersplenism may require partial or complete splenectomy, although removal of the spleen should be avoided because it results in rapid progression of the pulmonary disease.

Patients with NPD type B disease who undergo splenectomy frequently have worsening of pulmonary symptoms. Hepatosplenomegaly is prominent in childhood, but with increasing linear growth, abdominal protuberance decreases and becomes less conspicuous. In mildly affected patients, splenomegaly may not be noted until adulthood and disease manifestations may be minimal.

NPD type A/B

Patients with NPD type A/B (also known as intermediate phenotype, or chronic neurovisceral, ASMD) have symptom onset in early childhood and slower progression of mild neurologic symptoms than do patients with NPD type A, following a period of normal development. Neurologic symptom progression may last from 2-7 years. Neurologic symptoms may include peripheral neuropathy, extrapyramidal signs, psychiatric symptoms, learning disabilities, and ataxia. Patients also develop an ocular “cherry-red spot,” also known as a macular halo.

The liver and spleen are usually affected, with hepatosplenomegaly occurring. Liver disease may progress to portal hypertension and fibrosis, with liver function tests elevated. Patients may also develop diarrhea.

Lung involvement is similar to that in type A, and patients may develop interstitial lung disease and a restrictive pattern on pulmonary function testing. Radiographic findings may be marked in the absence of apparent clinical lung symptoms.

Some patients with NPD type A/B may have associated neurologic findings, including cerebellar signs, nystagmus, extrapyramidal involvement, and intellectual disability.

In some cases, patients with NPD type A/B also have cardiac involvement, in the form of valve disease and early onset coronary artery disease. Mixed dyslipidemia and low high-density–lipoprotein cholesterol (HDL-C) levels may develop.

Skeletal manifestations include delayed bone growth, growth restriction, and osteopenia, along with bone and joint pain and pathologic fractures.

Thrombocytopenia and bleeding tendencies, recurrent ear infections, and headaches are also noted in these patients.

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Physical Examination

Ocular findings

Patients with NPD type A disease usually have a cherry-red spot on ophthalmologic examination. In NPD type A patients, deposition of excess gangliosides occurs in the retina surrounding the macula. This results in opacification of a retina-sparing, cherry-red macula, thus resulting in a distinct appearance known as a cherry-red spot or macular halo.

Hepatosplenomegaly

Hepatosplenomegaly is a common feature in NPD. In NPD type A, the condition typically becomes massive, while in NPD type B, it can widely vary. Some patients with NPD type B have massive enlargement, whereas others have milder enlargement that may remain unnoticed for years.

Neurologic findings

Patients with NPD type A have progressive neurodegeneration, and attainment of milestones does not progress beyond 10 months in any domain. Motor milestone attainment rarely progresses beyond the ability to sit with assistance. Progressive hypotonia and loss of deep tendon reflexes result in loss of previously achieved milestones. The neurologic degeneration is relentless, leading to a spastic state. Seizures are not common.

Most patients with type B disease have normal findings on neurologic examination, although some patients have been described with peripheral neuropathy, extrapyramidal signs, psychiatric symptoms, and learning disabilities. In addition, some patients reportedly have normal early development but loss of language skills and onset of ataxia beginning around the third year of life.

Growth findings

Patients with moderate-to-severe NPD type B typically experience growth retardation in childhood and attain a final adult height that is less than expected based on familial heights.

Other

Examination of the skin in patients with NPD type B disease may reveal extensive bruising. Patients with severe hypersplenism may also have petechiae.

Findings on auscultation of the lungs are usually normal in the absence of an intercurrent respiratory tract infection in all types of NPD.

Cardiac examination findings are usually normal in the absence of valvular dysfunction. The valvular dysfunction may be present in NPD types B and A/B.

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