Advancing Understanding and Care of Leukodystrophies

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Neurosciences Update

Leukodystrophies (LDs) are a complex, often progressive group of disorders affecting the white matter of the central nervous system with or without peripheral nervous system involvement. They number about 30 disorders and are individually rare, but collectively common, affecting roughly 1 in 7,500 live births, with significant morbidity and mortality.

Despite advances in the diagnosis of these disorders, they remain widely under-recognized, and there are extensive unmet gaps in diagnosis, clinical care, and curative therapeutics.

Improving diagnosis of leukodystrophies

The Leukodystrophy Center at CHOP was created in 2015 to improve diagnostic efficacy and clinical care for these children. The center has quickly grown into one of the largest programs of its kind in the world. It brings together a multidisciplinary group of caregivers to provide cutting-edge, comprehensive diagnostic testing, clinical care, and the most advanced treatment to infants and children with inherited white matter disease.

Just 40 years ago, many of the LDs had not even been described and nothing could be offered in the way of treatment for those afflicted with these devastating conditions. Today, children can be diagnosed with once-unimaginable precision, and, although these diseases are not currently curable, collectively they are symptomatically treatable.

Rapid recognition and diagnosis of LDs is important to afford patients an opportunity for early treatment and care. Although a genetic diagnosis is not always achievable, a full evaluation is important because of its implications for treatment, prognosis, and family planning.

Disorders such as x-linked adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy (MLD), cerebrotendinous xanthomatosis (CTX), and Krabbe disease are rapidly diagnosable biochemically and have important disease-specific therapies available, including enzyme replacement, bone marrow/stem cell transplant, or gene therapy. Many of these therapies require prompt triage and initiation in order to take full effect, adding a level of urgency to an accurate diagnosis and therapeutic knowledge.

Comprehensive care

The Leukodystrophy Center sees patients from all over the country and the world. Our services include a newborn diagnostic clinic that provides rapid consultation by metabolic experts and neurologists for infants with a positive screening result.

Our comprehensive care clinic provides state-of-the art care and takes an all-encompassing view of the patient through a multidisciplinary team that includes neurology, metabolism, complex care pediatrics, rehabilitation medicine, physical therapy, occupational therapy, speech therapy, and nutrition, with additional nursing and social work support.

Our therapeutics program provides cutting-edge therapeutic strategies for distinct LDs as well as care algorithms for monitoring and initiating enzyme replacement, bone marrow or stem cell transplantation, or gene therapy.

Evaluation includes MRI pattern analysis and broad spectrum next generation sequencing (NGS) genetic testing, including delivery of clinical whole genome sequencing to undiagnosed patients and their families.

Delivering the news of a confirmed genetic diagnosis to a family is an important milestone that occurs promptly after confirmation and includes the input of our experienced genetic counselors. We go over diagnosis, prognosis, and recurrence risk/reproductive options, and create a thorough treatment plan that addresses acute, chronic, preventive, and psychosocial needs. Our long-term care goals are to enhance the quality and prolong the duration of life.

Ongoing LD research

Even with high-quality imaging, expert imaging interpretation, and a complete battery of clinical investigations, at least 20% of LD cases remain unresolved. For patients who do not achieve a specific diagnosis, we offer the option to participate in ongoing research programs, which aggregate patients with undiagnosed diseases with the aim of identifying new disease genes. We are on the verge of pilot or Phase I/II clinical trials for a number of previously untreatable LD disorders.

We are also gathering standardized natural history data, clinical assessment outcome measures, and radiologic/biologic biomarkers and are engaged in data-driven clinical research and translational therapeutics projects to discover molecular therapeutics that target the genetics of LD subtypes.

We lead the Global Leukodystrophy Initiative, an international consortium that includes a diverse group of LD experts, patient families, researchers, and patient advocates, to raise awareness of this disease and ensure that patients around the world receive appropriate social and medical support.