Early recognition of patients with leukodystrophies

Abstract

Leukodystrophies are defined as differences in normal myelin development and maintenance in the central nervous system. They typically present as white matter imaging abnormalities in young children with delayed developmental milestones. As the scientific community begins to better understand and research the mechanisms underlying leukodystrophies, clinical trials and approved therapies for specific disorders are becoming available. These interventions, ranging from repurposing of existing small molecules to recently approved gene therapies, are highly dependent on early diagnosis. It is essential for pediatricians to identify affected individuals promptly, but they face challenges including lack of awareness of the disorders and nonspecific symptom presentation (e.g., cognitive or motor developmental delay). This review provides five hypothetical clinical presentations and describes the disease mechanisms, typical symptoms, and treatments currently available for common leukodystrophies: Krabbe Disease, Aicardi Goutières Syndrome (AGS), Metachromatic leukodystrophy (MLD), Alexander Disease (AxD), Pelizaeus-Merzbacher Disease (PMD), and X-Linked Adrenoleukodystrophy (X-ALD.) This review educates pediatricians to recognize the presentation of leukodystrophies in affected children. These clinical vignettes can serve as a framework for pediatricians to identify potentially treatable rare disorders among their patients.

Introduction

Leukodystrophies are defined as progressive, genetic conditions associated with abnormal white matter (WM) development in the central nervous system (CNS). Involvement of oligodendrocytes, astrocytes, and other non-neuronal cell types is ultimately associated with abnormal findings in neuroradiologic imaging, specifically magnetic resonance imaging (MRI).¹ Leukodystrophies include a broad range of more than thirty disorders associated with a wide spectrum of clinical manifestations, spanning from mild to very severe neuromotor impairment.²

While initial symptoms are often nonspecific, atypical acquisition of cognitive and motor milestones and muscle tone abnormalities are common among affected children in the first years of life.^{9,11,14–15,17,19}

As we begin to better understand pathogenic mechanisms underlying leukodystrophies, there has been an emergence of clinical trials and approved therapies for specific disorders with very narrow windows for successful intervention.³ Pediatricians are often the first line of defense against these disorders, and their ability to recognize and refer affected individuals to specialists is critical to timely care.^4–5

This review describes possible clinical presentations of leukodystrophies to the pediatrician. Clinical vignettes introduce the following conditions: Krabbe Disease (otherwise called Globoid Cell Leukodystrophy), Aicardi Goutières Syndrome (AGS), Metachromatic Leukodystrophy (MLD), Alexander Disease (AxD), Pelizaeus-Merzbacher Disease (PMD), and X-Linked Adrenoleukodystrophy (X-ALD). The scenarios were created using the most common semiology of these disorders at the expected age of presentation with the goal of providing primary care providers with familiarity for leukodystrophies.

Methods

The clinical vignettes were created following previously published methodologies from Evans et. al.⁶ The clinical cases described were crafted referring to recent published papers in scientific literature, including reviews of each specific disorder. Clinical variables for each vignette were determined ahead of time and included symptoms at disease onset, birth history, age of presentation, exam findings, and parental reports. The draft vignettes were then reviewed by pediatric neurologists and pediatricians to enhance external validity.

Clinical vignettes

Clinical vignette #1:

A three-month-old colicky infant with no birth complications presents to the pediatrician’s office with inconsolable crying and irritability. The parents report that crying is excessive to the point where the child cannot be put down, and that these bouts of irritability are intermittent. In between bouts of irritability, the child must also be woken up to be fed, and there is limited weight gain. Upon exam, the infant does not exhibit a social smile, has poor head control, and does not seem to interact with the examiner through visual contact.

This affected individual should be considered for two early infantile onset leukodystrophies: Krabbe disease and Aicardi Goutières Syndrome. Both diseases can occur without a family history of the same, but careful review of the same is critical. Krabbe disease is a monogenic autosomal recessive condition associated with mutations in the GALC gene. This condition is associated with neuroradiologic signs of demyelination.⁷ Low galactrocerebrosidase (GALC) enzymatic activity in leukocytes has been identified in all patients with symptomatic Krabbe Disease.⁸ Clinical presentation can include developmental delay, irritability, axial hypotonia, or spastic paraparesis.⁷ Currently, some states utilize GALC activity screening assays in newborn screenings, so a newborn screening card or results can contribute to making a diagnosis.⁹ Other methods to identify Krabbe disease includes genetic testing of GALC via single gene, panels, exome, and genome testing.⁹ Krabbe disease is one of the most severe leukodystrophies, and any suspicion of the disorder should include an emergent referral to a pediatric neurologist or geneticist to facilitate diagnosis. Hematopoietic stem cell transplants have been shown to improve outcomes in patients, and clinical trials investigating gene therapies are currently underway.^9,26

Another disorder in the differential of this presentation should be Aicardi Goutières Syndrome (AGS). AGS is characterized by early onset encephalopathy due to a type-1 interferonopathy, associated with mutations in multiple genes involved in the signaling and metabolism of nucleic acids.¹⁰ Early clinical features of the condition include developmental delay, sterile pyrexia, chilblain-like lesions, and multi-organ involvement.^11–12 Exclusion of prenatal/perinatal infection should always be considered, since AGS can mimic signs and symptoms of congenital infections such as cytomegalovirus (CMV).¹¹ Diagnostic confirmation methods include genetic testing (single gene, panels, genome, or exome sequencing), or abnormal levels of neopterin in cerebrospinal fluid collected through lumbar puncture.¹¹ Recent clinical trials have shown Baricitinib to be a disease modifying treatment for AGS. Baricitinib is a Janus kinase inhibitor that selectively blocks the interferon receptors. Use of Baricitinib can be associated with thrombocytosis, leuko-penia, and increased occurrence of infection, and treated individuals should be regularly monitored.¹³

Clinical vignette #2:

A nine-month-old boy presents to the pediatrician with no birth complications. The parents report that he has achieved no developmental motor milestones yet, except limited head control, exhibit only with significant trunk support. Upon exam, the child exhibits hypotonia, but is socially engaged. Nystagmus is noted in the exam.

The main concern for this affected individual is Pelizaeus-Merzbacher disease (PMD). PMD is caused by variants in the PLP1 gene and is a monogenic X-linked recessive condition. Clinical symptoms include muscle tone abnormalities, nystagmus, truncal ataxia and delays in cognitive and motor development.¹⁴ Traditional PMD is only present in boys, but Pelizaeus-Merzbacher-Like Disease (PMLD) can mimic PMD semeiology and can occur in both boys and girls.¹⁵ Patient management will require the involvement of a multidisciplinary team. Affected individuals should be referred to a pediatric neurologist immediately. No disease modifying treatments are currently available for this condition, but clinical trials will open soon.²⁷

Clinical vignette #3:

An eighteen-month-old infant presents at a well visit to the pediatrician. There were no birth complications. Early development is reported as typical. Specifically, the child could sit independently on time, but pulled to stand later than expected. At this visit, the infant has recently presented a loss of those gross motor skills. Independent ambulation was never obtained. The parents also noted episodic strabismus and a decline in language production (from a qualitative and quantitative standpoint).

The situation described above should raise concerns for a diagnosis of Metachromatic Leukodystrophy (MLD). MLD is an autosomal recessive lysosomal disorder, caused by mutations in the ARSA gene, resulting in arylsulfatase A (ASA) deficiency.³ The diagnosis is confirmed by the occurrence of abnormal levels of urine sulfatides, ASA enzymatic testing, and ARSA genetic testing. MLD is a progressive and deadly disorder with a narrow window for intervention.³ Currently, gene therapy treatment (Libmeldy) has been approved in Europe.²⁴ Bone marrow or hematopoietic stem cell transplants are also a treatment option³ though efficacy is disputed.

Clinical vignette #4

An eighteen-month-old infant with no birth complications presents to the pediatrician with parents complaining of a febrile seizure. The parents also report that there has been a plateau in the acquisition of new developmental milestones in the previous few months. The child has recurrent, unexplained bouts of vomiting. After a clinical exam, macrocephaly (head circumference above 2 Standard Deviation) is noted.

A possible diagnosis for this individual is Alexander Disease (AxD). AxD is a monogenic autosomal dominant condition caused by mutations in the GFAP gene, which is associated with astrocyte abnormalities and leads to white matter degeneration.¹⁶ Clinical manifestations include seizures, developmental delay, macrocephaly, recurrent vomiting, dysarthria, and dysphagia.¹⁶ Genetic testing (single gene, panels, genome, or exome sequencing) can be used to identify a variant in the GFAP gene and confirm the diagnosis.¹⁷ There is currently no approved disease modifying treatment, and clinical trials are currently ongoing in human subjects. No preliminary data around safety and efficacy of the treatment is currently available.²⁹

Clinical vignette #5:

A six-year-old boy presents to the pediatrician for a well visit. There were no birth complications, and all developmental milestones were achieved. The physical exam is unremarkable. However, parents report that his teachers have complained that he has had behavioral concerns consistent with hyperactivity in the past weeks. Additionally, his teachers have observed a change in the quality of his handwriting.

The main concern for this boy is X-linked adrenoleukodystrophy (X-ALD, ALD). ALD is caused by a variant in the ABCD1 gene on the X-chromosome, leading to a peroxisomal disorder in very long-chain fatty acid (VLCFA) transport.¹⁸ VLCFA levels should be tested in blood, as elevated results of certain fatty acids can be indicative of X-ALD.¹⁹ Genetic testing for ABCD1 should be ordered as well. While attention deficit disorder (ADD) may be the diagnosis, this child should be urgently referred to a pediatric neurologist in view of the subacute onset of behavioral changes and changes in fine motor ability. ALD currently was added to the recommended uniform newborn screening panel (RUSP) and is screened at birth in over thirty states.¹⁶ A gene therapy (Skysona) was recently submitted for Food and Drug Administration (FDA) approval in the United States.²⁸

Discussion

Identifying leukodystrophies in affected individuals is challenging due to lack of provider education and heterogeneity of symptom presentation. While classically identified as rare diseases, advances in genetic testing indicate that leukodystrophies might be more common than originally hypothesized. Previous findings have identified the incidence of pediatric demyelinating disorders at about 1–1.5/100,000, although some estimates place it as high as 1 in 4,733 individuals.^20–21 Furthermore, leukodystrophies are easily confused with other disorders that share similar symptoms at disease onset, such as cerebral palsy.²⁵

Finally, many leukodystrophies have a narrow window for therapeutic intervention³, as they are progressive in their impact on cognitive and motor development.^{9,11,14–15,17,19}

Due to recent approval of specific disease-modifying therapies,^13,24 early recognition and treatment of leukodystrophies has become critical in the clinical management of affected subjects.

For many affected individuals with leukodystrophies, symptoms will first be noticed by or brought to the attention of their pediatrician. Early intervention has proven to have many short and long-term benefits for the motor and cognitive skills of children with developmental delays and disabilities.^4–5 Additionally, the quality of life of caregivers of an affected individual, often parents, can be negatively impacted by diagnostic delay; parents have reported that knowledge around a child’s diagnosis and care needs is important for their emotional needs and coping process.^22–23 Furthermore, given the early lethality of some specific leukodystrophies, referral to a specialist may permit appropriate intervention in a narrow therapeutic window. For example, in affected individuals with Metachromatic leukodystrophy (MLD), approved ex-vivo gene therapies are likely to be beneficial only before or immediately after symptom onset.³ Lastly, leukodystrophies are best treated by a multidisciplinary care team including but not limited to occupational therapy, physical therapy, speech therapy, complex care medicine, physical medicine and rehabilitation, neurology, nutrition, and genetic counseling.^{9,11,14–15,17,19}

In summary, for infants who are presenting with irritability and encephalopathy, toddlers presenting with worsening clumsiness or regression, and school-aged boys presenting with new inattention and progressive clumsiness, leukodystrophies should be high on the differential diagnosis.^{9,11,14–15,17,19} Primary care physicians should reach out to their local neurology team and request an expedited neurology evaluation since treatment is time sensitive. Check the newborn screen for X-ALD and Krabbe A, as those will become increasingly available.^9,19