Lipid Storage Disorders Treatment & Management

Updated: Jun 10, 2020
  • Author: Rubia Khalak, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Treatment

Medical Care

Except for Gaucher and Fabry disease, treatment options are limited in patients with lipid storage disorders. Primarily, treatment is directed at symptomatic relief. No specific treatment is available for either form of GM1 gangliosidosis, Tay-Sachs disease, Sandhoff disease, fucosidosis, Krabbe disease or Schindler disease. These disorders pursue a relentless course, leading to death.

Gaucher disease

When possible, patients with Gaucher disease should be managed by a multidisciplinary team at a comprehensive Gaucher Center.

Enzyme replacement therapy (ERT) with recombinant beta-glucocerebrosidase (Cerezyme, Genzyme, Cambridge, Mass; VPRIV, Shire, Cambridge, Mass) is available for the treatment of symptomatic patients with Gaucher disease type 1. [37]

Regular intravenous infusions of recombinant enzyme have been shown to clear the stored substrate GL1, and thus reverse hematologic and liver/spleen involvement. Although skeletal disease is slower to respond, early treatment may be efficacious in normalizing linear growth and bone morphology in affected children.

Although enzyme replacement does not alter the neurologic progression of patients with Gaucher disease types 2 and 3, it has been used in selected patients as a palliative measure, particularly in patients with severe visceral involvement. Individuals with severe visceral symptoms due to Gaucher disease type 3 often benefit from bone marrow transplantation. In some individuals, a combination approach using both enzyme replacement therapy and bone marrow transplant has been used. However, the use of bone marrow transplant is limited due to the associated morbidity and mortality.

Substrate reduction therapy (SRT) is a new approach in which glycolipid accumulation is counteracted, not by replacing the deficient enzyme, but by reducing the substrate level to better balance residual activity of the deficient enzyme.

​Miglustat was approved in 2003 as a second-line monotherapy in adults with mild-to-moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option.

Eliglustat was approved in August 2014 as first-line treatment for the long-term treatment of adults with Gaucher disease type 1. The dose of eliglustat is determined by establishing the patient’s CYP2D6 phenotype (ie, extensive metabolizers [EM], intermediate metabolizers [IM], or poor metabolizers [PM]). Approval was based on efficacy data from 2 positive phase 3 studies involving 199 patients. One study involved patients new to therapy (trial 1), and the other involved patients switching from approved enzyme replacement therapies (trial 2). Efficacy data from 4 years of the Cerdelga phase 2 study also contributed to the approval. Improvements in study participants were observed in spleen size, platelet levels, hemoglobin levels, and liver volume, and noninferiority to enzyme replacement therapy (imiglucerase) was established in trial 2. [38]

SRT was shown to be effective concerning hepatosplenomegaly, anemia, and thrombocytopenia; by contrast, improvements of bone disease were delayed and limited. [20]

Studies are currently underway to investigate the use of miglustat for the treatment of infantile-onset GM2 gangliosidosis and childhood Niemann-Pick type C. One retrospective review reported that a year or more of miglustat treatment in infantile and juvenile patients with Niemann-Pick disease type C reduced disease progression. [39]

A case study of combined ERT and SRT revealed improvement of neurological signs in symptomatic patients with Gaucher disease type 3 and, over a 3-year observation period, demonstrated prevention of further neurological manifestations in a young child whose only initial manifestation was disturbed saccadic eye movements [20]

Fabry disease

Until recently, treatment for Fabry disease has been nonspecific and limited to supportive care. These measures included the use of phenytoin and carbamazepine, which have been shown to decrease the frequency and severity of the chronic acroparesthesias and the periodic crises of excruciating pain. Renal transplantation and long-term hemodialysis also have become life-saving procedures for patients with renal failure. Statins and aspirin have been used to reduce thromboembolic risk factors. Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers have been used to treat proteinuria and hypertension.

Enzyme replacement therapy with recombinant alpha-galactosidase A (Replagal, TKT Corporation, Cambridge, Mass; Fabrazyme, Genzyme Corporation, Cambridge, Mass) is available. Fabrazyme is the only ERT for Fabry disease approved by the FDA. [37] Data from clinical trials show a decrease in GL-3 levels following enzyme replacement therapy, reversal in lipid tissue storage, and stabilized or improved renal and cardiac function. Subjective reduction or relief from neuropathic pain has been documented, in addition to a decrease in the long-term use of neuropathic pain medication.

Oral migalastat is used to treat Fabry disease in some patients aged 16-18 years or older, depending on the specific gene mutation. [40]

Recent advances in recombinant enzyme replacement, bone marrow transplantation, gene transfer, substrate reduction, and chaperone-mediated therapy provide great hope in potentially treating other lipid storage disorders.

Wolman disease

Dietary restriction has shown promise for disorders such as lysosomal acid lipase deficiency (Wolman disease), as has incorporation of lipid-lowering drugs in the regimen along with sebelipase alpha, a recombinant enzyme replacement therapy. [7]

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Consultations

Patients thought to have a lipidosis should have an evaluation with a clinical geneticist.

Neurologic consultation also is indicated.

Patients with Fabry disease should have a cardiac evaluation.

Patients with Gaucher disease type 1 and sphingomyelinase deficiency (NPD type B) should have pulmonary consultations.

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Diet

Nutritional therapies involving particularly specific subsets of macronutrients and/or micronutrients are used in the treatment of some lipid storage disorders. However, the variances in nutritional treatments and the limited population of affected individuals result in limited data with outcomes often based on case reports.

Neutral lipid storage disease with myopathy (NLSD-M): Patients may benefit from a diet that is particularly adequate in carbohydrates as a consistent source of energy production. This recommendation is believed to stem from a study in which patients who received intravenous glucose exhibited respiratory improvements. [41]

Neutral lipid storage disease with ichthyosis (NLSD-I), also known as Chanarin-Dorman syndrome: Patients may benefit from high-carbohydrate, low-fat diets with supplemental medium-chain triacylglycerol (MCT). Other case reports have noted use of low-fat, long-chain fatty acid (LCFA)–restricted and carbohydrate-rich, protein-restricted diets with little therapeutic benefit. Finally, a case report has found that a gluten-free diet improved gastrointestinal symptoms and marginally enhanced muscle strength. [41]

Primary carnitine deficiency (PCD): A case report described a patient with amelioration of cardiac symptoms after interventions including medium chain fatty acids (MCFAs). [41]

Multiple acyl-CoA dehydrogenation deficiency (MADD): Riboflavin supplementation in riboflavin-responsive (RR) MADD improves symptoms in adult-onset cases. Coenzyme Q10 (CoQ10) and vitamin B12 are also used in adult-onset cases to improve outcomes. In addition, dietary education may be warranted to prevent the potential dangers of carbohydrate restriction in this population. [41]

Neurofibromatosis type 1 (NF1): Muscle lipid phenotypes may see improvements after a reduction in dietary long-chain fatty acid intake in addition to L-carnitine supplementation. [41]

Inclusion body myositis (IBM): A phase 1 trial is scheduled to investigate whether triheptanoin oil can recover muscle performance in patients with IBM. [41]

Patients with sphingomyelinase deficiency (NPD) have elevated total cholesterol, although effects of dietary restriction of cholesterol have not been demonstrated in animal models of NPD type C. [42]

Avoidance of prolonged fasting is recommended for all fatty acid disorders. [43]

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Activity

Gaucher disease and patients with sphingomyelinase deficiency (NPD types A and B) with organomegaly should avoid contact sports and seek immediate medical attention for trauma. If their platelet counts drop precipitously secondary to hypersplenism, they are at risk for both splenic rupture and intracranial bleeding.

Weight-bearing exercise has been recommended in patients with acid sphingomyelinase deficiency to prevent osteopenia. [44]

Aerobic exercise lasting more than 30 minutes should be avoided in patients with fatty acid disorders. [43]

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Further Outpatient Care

Fabry disease

Baseline diagnostic studies (electrocardiography, echocardiogram, ophthalmologic examination, renal function tests, plasma and/or urine GL-3) should be obtained. Affected family members identified during screening should also undergo identical evaluations; adults should also undergo additional testing as recommended.

Infants with Fabry disease should be seen by a metabolic specialist at 6-month intervals and monitored for the onset of Fabry symptoms. [20]

Gaucher disease

Evaluations for anemia/thrombocytopenia, hepatosplenomegaly, and bony involvement should be performed.

In patients who are predicted to have neuronopathic Gaucher disease and in patients whose genotype cannot accurately predict the phenotype, the degree of neurological impairment should also be assessed.

Gaucher biomarker and anti-GBA antibody levels should be measured before initiation of ERT.

Infants should be monitored at regular intervals (at least quarterly) to assess response to treatment and development. [20]

Niemann-Pick disease

Infants with Niemann-Pick disease should undergo dilated funduscopic examination performed by an ophthalmologist.

Plain chest radiography abdominal ultrasonography should be performed at regular intervals to document the extent of pulmonary involvement and hepatosplenomegaly.

The metabolic physician should evaluate the infant on a monthly basis, documenting weight gain, linear growth, pulse oximetry, and developmental progression.

Infants need evaluation and regular follow-up by a neurologist and pulmonologist as the disorder progresses. Because no curative treatment currently exists, only symptomatic and supportive care can be provided.

Lipid-lowering drugs (eg, statins) are ineffective. [20]

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