Overview

Did you hear before about Niemann-Pick disease ?

So basically lysosomal storage disease occurs due to  a deficiency of acid sphingomyelinase, which its function to catalyzes the hydrolysis of sphingomyelin to ceramide and phosphocholine. What will happen when there is a deficiency in acid sphingomyelinase? The lipid-rich macrophages accumulate in multiple organ include Liver, Spleen, Lungs, and Brain. Thus lead to Hepatosplenomegaly, Thrombocytopenias,Pulmonary disease, and Neurological symptoms.The most common visceral manifestations are Hepatosplenomegaly, Thrombocytopenia, and Interstitial Lung disease.¹

Types:

There are three types A , B and C. That is Classified according to the specific genetic cause of the disease. 

Type A 

Type A is usually develops symptoms in childhood. Those Symptoms include undergrowth of the Liver and Spleen, frequent respiratory infections, and Lung disease. Type A is caused by a mutation in SMPD1 gene directly affecting the production of acid Sphingomyelinase. Management mainly of Niemann Pick type A disease include supportive care and targeted treatment of specific symptoms.²

Type B

Both type B and type A are autosomal recessive leading to abnormal maintenance of sphingomyelin. Clinical presentation of The disease is characterized by Hepatosplenomegaly in infancy, and most patients develop thrombocytopenia due to hypersplenism. Patients that live longer can develop neurological disorders such as nystagmus, psychiatric illness and peripheral neuropathy.³

Type C

Neurological involvement determines disease severity in most patients, although it is usually preceded by systemic symptoms. Depending on patient Age the first neurological manifestation and onset include delayed motor milestones, gait disturbances, falls, clumsiness, cataplexy, school problems and ataxia, which often do not follow the first psychiatric disorders. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia and progressive dementia. The clinical examination should include a thorough neurological and ophthalmological evaluation.⁴

Genetic Basis and Pathophysiology

Genetic Mutations Causing NPD

As stepwise strategy based on common mutations needs to be developed for rapid and cost effective molecular genetic testing of NPD to confirm NPD diagnosis, aviation detection, prenatal diagnosis, and preimplantation genetic diagnosis in families with these diseases. However more than 100 mutations in the SMPD1 gene have been reported to cause NPA and NPB. The Mutations as small deletions or Nonsense mutations in the SMPD1 gene that lead to truncated proteins can cause type A. Also several common NPD mutations have been found in different populations. These mutations have been found mainly in Exon 2 of SMPD1 gene and Exon 8 and 9 of NPC1 gene.⁵

Impact on Cellular Lipid Metabolism

Sphingomyeline will bind to cholesterol with high affinity, causing a decrease in cholesterol secretion and subsequent efflux from lysosomes, leading to impaired cholesterol esterification by acyl-CoA:cholesterol acyltransferase in the Endoplasmic Reticulum. These events align in macrophages from ASMase −/− mice or wild-type mice enriched with exogenous SM, resulting in increased lysosomal cholesterol content due to decreased cholesterol efflux. The current model of cholesterol transport in lysosomes assumes that NPC2 binds cholesterol and transfers it to NPC1, which then transports cholesterol across the glycocalyx to the endosomal/lysosomal membrane and release it from organelle by mechanisms that still Unknown. Investigating the complex interactions between mitochondria and lysosomes can be critical not only for understanding important physiological processes, but also for discovering the role of mitochondrial dysfunction in the development of human pathologies, including LSD. Intracellular Cholesterol Transport into Mitochondria in NP Disease Despite its low concentration in mitochondrial membranes, the mitochondrial pool of cholesterol plays key physiological roles, including steroid synthesis in steroidogenic cells, bile acid synthesis in hepatocytes, and maintenance of structural and functional properties of membrane bilayers. Recently, protein complexes involved in membrane contact between the ER and mitochondria have been identified, but their role in lipid transport remains unclear. StARD3 overexpression increases steroidogenesis by stimulating mobilization of lysosomal cholesterol to mitochondrial P450scc, while mutant StARD3, which lacks the START domain, induces cholesterol accumulation in lysosomes.⁶

Respiratory Involvement in Niemann-Pick Disease

General Respiratory Complications

There are many complications associated with lungs in NPD such as Alveolar proteinosis, interstitial lung disease, chronic obstructive pulmonary disease, respiratory infections and respiratory failure ,pulmonary fibrosis, other lung disease, other specified respiratory disease, primary or secondary pulmonary hypertension, pulmonary heart disease, other chronic obstructive disease. pulmonary disease, other respiratory disease, pulmonary embolism, other pulmonary heart disease, respiratory bleeding, other secondary pulmonary hypertension, restrictive lung disease and unspecified pulmonary hypertension. The significant increase in respiratory disease during long-term follow-up show the progression nature of ASMD and the need to close monitor respiratory complications and optimal treatment to decrease morbidity and mortality. Pneumonia, Chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome, pulmonary fibrosis, respiratory failure, other lung diseases, other specified respiratory diseases, pulmonary hypertension classified as primary or secondary, pulmonary heart disease, other chronic obstructive pulmonary disease, other respiratory diseases, pulmonary embolism, other pulmonary heart diseases, respiratory bleeding, other secondary pulmonary hypertension, restrictive lung disease and unspecified pulmonary hypertension. The incidence and prevalence of almost all lung and respiratory diseases in older groups, especially those over 65, was significantly higher than in younger groups, which probably reflects the progressive deterioration of the respiratory system, increased susceptibility. against age-related infections and co-morbidities associated with aging. The study followed 8,980 patients with ASMD for up to 20 years.⁷

Specific Lung Complications

Respiratory symptoms range from no symptoms to respiratory failure. Progression of airway disease is slow but irreversible due to the accumulation of Niemann-Pick cells in the alveolar septa, bronchial walls and pleura, which can lead to progressive worsening of restrictive patterns on pulmonary function tests. Bronchoalveolar lavage has an important diagnostic value. X-ray findings consist of a reticular or reticulonodular pattern and finally a tile pattern involving mainly the lower lung regions.⁸

Clinical Presentation and Diagnosis

Symptoms Related to Lung Complications

The most common respiratory symptoms were recurrent pneumonia and shortness of breath.

Although six patients with NPD had normal lung examination results, they had lung disease; Three patients were diagnosed with NPD directly by lung biopsy during investigation of recurrent lung infection or interstitial lung disease.

All but one GD patient had respiratory symptoms at diagnosis.

Ground glass pattern and atelectasis were two important high-resolution computed tomography findings in patients with NPD and GD.⁹

Diagnostic methods

In conclusion, interstitial lung disease and pulmonary function abnormalities at rest are common features of Niemann-Pick type B disease. Finding of imaging features that do not necessarily correlate with the degree of lung function decline may reflect the nature of interstitial lung disease, which is not usually characterized by fibrosis. Therefore, radiographic and thin-section CT findings must be interpreted based on functional data and the patient's clinical status. Radiological features alone should not be the basis for more invasive diagnostic tests such as biopsy, as little additional information of clinical benefit is likely to be obtained, especially in patients without pulmonary symptoms. Radiographs were evaluated by evaluating each lung individually for evidence of interstitial disease, including reticular, nodular, and prominent bronchovascular changes. A 0-3 integer scale was used to quantify the overall degree of interstitial lung disease present in each lung region as follows: a score of 0 indicated no interstitial lung disease; grade 1, mild interstitial lung disease; score 2, moderate interstitial lung disease; and score 3, severe interstitial lung disease. The total score for each patient was obtained by averaging the scores for both lungs. Each image received three independent scores that assessed the overall presence of interstitial lung disease, the presence of thickened lobular septa and intralobular lines, and the presence of areas of ground-glass opacity on both the right and left sides. The four levels of each lung were evaluated separately, for a total of eight values ​​for each patient. Mild lung disease was diagnosed when the mean score was less than or equal to 1. And Moderate disease was diagnosed when the mean total score was greater than 1 and less than or equal to 2. Lastly Severe disease was diagnosed when the mean total score was greater than 2. As results of functions and patient age was assessed by correlation analysis using Spearman's rank correlation coefficient.¹⁰

Management and Treatment

Symptomatic Treatment

• Oxygen therapy
• Medications for infections and inflammation

Supportive Care

• Respiratory physiotherapy
• Nutritional support

Emerging Therapies

• Enzyme replacement therapy (ERT)
• Substrate reduction therapy (SRT)

Summary

As recap Niemann-Pick disease is a lysosomal storage disease caused by a deficiency of acidic sphingomyelin, which catalyzes the hydrolysis of sphingomyelin to ceramide and phosphocholine. Niemann-Pick disease type A and B are autosomal recessive disorders caused by a deficiency of acid sphingomyelinase which results in abnormal maintenance of sphingomyelin. 

Respiratory tract involvement in Niemann-Pick disease are alveolar proteinosis, interstitial lung disease, chronic obstructive pulmonary disease, respiratory infections and respiratory failure, COPD, acute respiratory distress syndrome, pulmonary fibrosis, respiratory failure, primary or secondary pulmonary hypertension, other secondary pulmonary hypertension, restrictive lung disease, Pneumonia.