Research Summary: April 2022

Research summary of recent leukodystrophy research and clinical trials, includes article summaries and direct links to websites and articles.


Adult onset autosomal dominant leukodystrophy (ADLD)

Genome sequencing reveals novel noncoding variants in PLA2G6 and LMNB1 causing progressive neurologic disease

This article highlights the importance of genome sequencing as a diagnostic tool for progressive neurologic disease. Genome sequencing is a technique which allows identification of the DNA sequence. DNA sequence is the specific order that nucleotides have, in a DNA molecule. A study was done analysing DNA obtained from leukocytes, also known as white blood cells, of two different patients, exhibiting signs of neurological disease. The first patient was a 5-year-old male with developmental delays appearing at the age of 12 months. At 4-years-old he could not use his hands or support his neck, enabling the usage of a wheelchair mandatory. Scientists tried various tests including genome sequence, which revealed an impairment to a gene called PLA2G6. The gene was considered to be pathogenic, underlying neuroaxonal dystrophy (impairment affecting a part of neuron called axon) characterised by progressive neurodegeneration (progressive loss of function or structure of neurons). Identification of this gene resulted to definite diagnosis and therefore targeted treatment was feasible. The second patient was a 47-year-old male demonstrating signs of neurological disease starting at the age of 42. As in the first patient, multiple tests were done but mutation on a gene called LMNB1 was only detectable using genome sequencing. The pathogenic mutated gene was found responsible for causing adult-onset demyelinating leukodystrophy, characterised by degeneration of white matter appearing on the fourth or fifth decade of life. Identification of the gene and hence, identification of the condition resulted to earlier diagnosis. The outcome of the research, which is the importance of genome sequencing for dictating neurological disease, established the broad usage of genome sequencing leading to earlier and definite diagnosis.


Aicardi-Goutieres Syndrome (AGS)

Mutations in RNU7-1 Weaken Secondary RNA Structure, Induce MCP-1 and CXCL10 in CSF, and Result in Aicardi-Goutières Syndrome with Severe End-Organ Involvement

This article reviews the pathogenic nature of Aicardi-Goutieres Syndrome (AGS) and how it can result to severe organ damage and increased mortality. AGS is a type I interferonopathy which refers to the uncontrolled interferon production leading to autoinflammatory diseases and early-onset neurologic regression. In healthy individuals, interferons are substances produced by the organisms’ cells to fight viruses. Mutations on the gene RNU7-1 were identified to cause impairments in structures called histone in the genetic material of the cells. Histones are proteins found inside cells and their predominant role is to control the expression of genes. When impaired they release abnormal quantities of substances which cause interferon overproduction. According to research including three uncategorized AGS patients, impairment of the RNU7-1 gene is interrelated with the appearance of AGS. This was proven using biological techniques, such as whole exome sequencing and Sanger sequencing, used to identify the exact genetic information of both the mutant and the normal variant of the gene. All reported patients with that specific mutation leading to AGS were linked with high mortality as well as organ failure at a young age. Overall, genome sequence of the RNU7-1 is advised to be used in uncategorized cases of AGS to determine if the condition is caused by mutations in that gene. Early diagnosis and organ screening can lead to successful treatment increasing the survival rate and the patient’s quality of life.


Adrenoleukodystrophy (ALD)

Variables affecting outcomes after allogeneic hematopoietic stem cell transplant for cerebral adrenoleukodystrophy

This article analyses how allogeneic hematopoietic stem cell transplant (allo-HSCT) can act as a treatment for cerebral adrenoleukodystrophy (CALD), reviewing in the meantime the variables affecting the success of the treatment. CALD is the most severe form (affecting 35% of male patients) of adrenoleukodystrophy, a metabolic disorder caused by genetic mutations on the ABCD1 gene. If not treated in time, neurological loss can lead to major functional disabilities and death at an early age.  Treatment using allo-HSCT was proven to reduce both the symptoms as well as the progression of the disease, when performed at an early stage. However, various variables such as the donor source, disease status and condition regimen, which includes the specific treatment the patient must follow to enable transplantation success, influence the outcome of allo-HSCT. This was proven by large international research made in male patients, under the age of 17, diagnosed with CALD. Identification of the efficacy and safety of allo-HSCT treatment resulted in important clinical data used to evaluate its success. Through the research it is confirmed that allo-HSCT treatment is successful when used to treat the disease at an early stage. Therefore, the importance of newborn screening was highlighted, as early diagnosis provides the opportunity of successful allo-HSCT treatment, slowing down the progression of the disease and increasing the survival rate.


Monitoring for and Management of Endocrine Dysfunction in Adrenoleukodystrophy

This article refers to the endocrine dysfunction in adrenoleukodystrophy (ALD), how it can be monitored and how the effects can be managed. It is a US based paper which highlights the needs for newborn screening more widely. ALD is caused by a pathogenic variant of the ABCD1 gene, disrupting production of the specific protein for metabolising very long-chain fatty acids (VLCFA) . This leads to accumulation of VLCFA to tissues such as the adrenal gland, impacting the production of hormones. Adrenal insufficiency in patients with ALD is commonly present due to the toxic effects of the VLCFA accumulation to the adrenal cells. In the article, the study showed that adrenal insufficiency occurs in the majority of male ALD patients, starting in the foetal period (time period from 9th week of pregnancy until birth).  Symptoms of endocrine dysfunction and adrenal insufficiency in males, can be detected as early as 3.5 years and treatment with hormone replacement is feasible for managing adrenal insufficiency. In order to detect and correctly diagnose ALD adrenal insufficiency a procedure known as newborn screening is applied. Newborn screening includes various blood tests to diagnose conditions such as ALD. It allows identification of patients being in high risk to appear adrenal insufficiency, enabling early treatment successful. Overall, ALD is able to cause serious endocrine abnormalities and possible death as hormonal production is heavily impaired. For this reason, proper management and monitoring of endocrine dysfunction is crucial to reduce the severity of the symptoms, leading to better life quality for patients.


Newborn Screening for X-Linked Adrenoleukodystrophy: Review of Data and Outcomes in Pennsylvania

X-linked Adrenoleukodystrophy (X-ALD) is a degenerative disease that impacts the nervous system due to a mutation of the ABCD 1 gene leading to Very-Long-Chain-Fatty Acids (VLCFA) accumulating. ALD can manifest at any stage of a person’s life, from childhood to adulthood. Newborn screening is thus essential as early diagnosis and intervention can change the outcome of the disease. Newborn screening identifies individuals when they are asymptomatic. In Pennsylvania, the outcomes of the first four years of X-ALD newborn screening were analysed using a two-tier approach and further genetic testing. During the first tier of screening, if a newborn has VLCFA levels beyond a particular concentration, they will be screened for a second time. If the newborn presents with levels of VLCFA beyond a specific concentration in tier two, they will then have to have the genetic composition analysed to determine if the ABCD 1 gene is indeed mutated. Those that reached the third stage would then be examined to see if the mutation of the gene would cause X-ALD. The study demonstrates multiple things regarding X-ALD screening in newborns. During the study, 49 newborns were diagnosed with X-ALD. The manifestation of X-ALD in younger siblings is a good indicator that the older siblings are either asymptomatic or carriers of the disease. Boys are more likely to present with X-ALD during childhood than girls. Girls are more likely to be carriers or manifest the disease in adulthood, so screening female newborns often does not provide clinically relevant information. Newborn screening for X-ALD can be a powerful diagnostic tool; however, it is not without limitations due to the complicated nature of the disease. With time and more newborns being screened, there is hope for improved diagnostic tools suitable for male and female newborns.


GM2 gangliosidosis

JCR to Initiate Development of New Drug Candidate for GM2 gangliosidosis

JCR Pharmaceuticals is a Japanese based company with many international branches. As of March 18, 2022, they have announced their decision to develop a new drug, JR-479, for GM2 Gangliosidosis using their J-Brain Cargo technology. GM2 Gangliosidosis is a rare genetic disorder that progressively destroys the cells located in the brain and spinal cord due to a build-up of GM2 ganglioside glycolipids. The drug they aim to develop will be able to enter the central nervous system (CNS) and be able to treat the affected areas in the brain and spinal cord. Enzymes are structures in the body that help important biological reactions occur necessary for life. When the enzyme that is meant to break down the GM2 ganglioside glycolipids is mutated, it can no longer perform its function, leading to an accumulation of the molecule. JR-479 aims to supplement this enzyme in the brain to decrease the accumulation. Animal studies have demonstrated that when administrating JR-479, the drug could enter the brain successfully, reducing the GM2 ganglioside glycolipids. The results of the animal trials have encouraged the company to aim for clinical trials in the next three years. The development of this drug would significantly impact individuals suffering from GM2 Ganglioside as there is currently no clinically established treatment for the disease. The development of JR-479 would enable these individuals to have a better quality of life.


Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC)

H-ABC– and dystonia-causing TUBB4A mutations show distinct pathogenic effects

This article refers to mutations on the TUBB4A gene and how they cause wide-spectrum diseases. They are mostly responsible for movement disorders and complex neurological conditions due to the cell’s inability to divide properly. The TUBB4A gene is mostly expressed in cells of the central nervous system and specifically in the white matter (tissue in the nervous system), cerebellum and basal ganglia which are regions of the brain. Therefore, mutations on TUBB4A affect the neuron system and result in conditions such as isolated dystonia (DYT-TUBB4A) and hypermyelination with basal ganglia and cerebellum atrophy alongside white matter deterioration (H-ABC). Isolated dystonia is a mild condition, characterised by the juvenile or adult onset of symptoms including general dystonia, where muscles in the body contract involuntary causing repetitive movements. On the other hand, H-ABC is a severe condition with an early onset -within the first 2 years of birth- characterised by severe developmental delays and physical impairments. Research was made, using cells called oligodendrocytes (a type of nervous cell), to analyse the influence of different mutations on the TUBB4A gene leading, hence, to wide disease spectrum. It was shown that different TUBB4A mutations resulted in different changes at cellular and molecular level justifying the existence of various types of the condition. Early identification of the exact mutation can lead to early diagnosis and therefore successful treatment is possible, slowing down the progression of the disease and increasing the survival rate.


Krabbe Disease

Clinical and molecular findings in 6 Turkish cases with Krabbe disease

Krabbe Disease is a rare condition that causes a degeneration of the nervous system and is a result of mutation of the beta-galactocerebrosidase (GALC) gene. The study looks at the infantile appearance of the disease in the Turkish population. It also aims to describe the clinical and molecular findings and compare the range of different types of genetic mutations with previous studies. In the Turkish clinic where this study took place, six patients had infantile Krabbe Disease. This study occurred during the years 2015 to 2019. The patients’ family history and clinical information were recorded during this time, and a series of biochemical and radiological examinations were performed and evaluated. The evaluations of the examinations revealed four known types of genetic mutations of the GALC gene and two new types of mutations. These new types of mutation had not previously been recorded in earlier studies. The results of this study can contribute to adding more information on the spectrum of genetic mutations that cause Krabbe Disease. The addition of two new types of mutations is also significant as well. By combining these two aspects, methods for screening newborns and parents who can potentially pass on this mutated gene can be done at earlier stages and with improved efficiency.


Leigh Syndrome

CHOP Researchers Show Early Developmental Delays Predict Poor Long-term Outcomes in Leigh Syndrome Patients

Leigh syndrome is a severe neurological disorder characterised by the loss of developmental milestones that were previously achieved. Researchers at the Mitochondrial Medical Frontiers Program have recently found that the developmental delays associated with Leigh Syndrome may begin earlier than previously thought. There are currently no clinically approved treatments available for Leigh Syndrome. The diagnosis that a child may have Leigh syndrome was usually reached after developmental regression began, with only a few cases where it occurred before. These rare cases had exhibited primary developmental delays before regression. Researchers at Children’s Hospital of Philadelphia (CHOP) decided to examine the pre-existing records to see if primary developmental delays occurred more commonly than previously thought. Their study aimed to find ways to diagnose Leigh Syndrome sooner. Three distinct manifestations were found during the study:

  1. Children experienced developmental delays that were then followed by regression.
  2. Children experienced developmental delays but did not experience a regression.
  3. Children experienced no developmental delays but did have a regression.

Children who present with developmental delays were more likely to present with Leigh Syndrome at an earlier stage and experience long-term educational difficulties. The study demonstrates that Leigh Syndrome should be looked out for as soon as developmental delays are detected in children. By doing this, the syndrome can be diagnosed at earlier stages, and therapeutic interventions can be implemented sooner. There is hope that this study’s findings can help design future clinical therapeutic trials that can be put in place earlier.


Metachromatic leukodystrophy (MLD)

Measurement of sulfatides in the amniotic fluid supernatant: A useful tool in the prenatal diagnosis of metachromatic leukodystrophy

This article reviews the research made to identify measurement of sulfatides in amniotic cells, as diagnostic tool for a condition called metachromatic leukodystrophy (MLD). MLD is a lysosomal disorder which suggests impaired function of lysosomes (cell structure containing enzymes), leading to abnormal accumulation or deficiency of enzymes. In patients with MLD there is a lack of the enzyme, coded by the gene ARSA that affects sulfatide metabolism. When the gene is impaired, the enzyme is not produced in the correct quantities resulting to sulfatide accumulation. It is important to mention that sulfatides are essential molecules present in various tissues and cells, especially in the nervous system where they are found in the myelin sheath. The myelin sheath is the protective layer that wraps neuron cells, preventing their loss of function. However, insufficient quantity of the enzyme involves accumulation of sulfatides to the nervous system, leading to progressive demyelination, which is the loss of the neuron cells’ myelin. In this research, amniotic cells were taken from the mother during the 19th week of pregnancy and their genome (genetic information of cell) was analysed, revealing the presence of the impaired ARSA gene. Hence, early diagnosis is considered crucial for the development of the condition as early treatment is feasible. Overall, this article highlights the importance of early diagnosis via amniotic fluid cell analysis enabling successful treatment, and slowing down the development of the disease.


Identification of neurodegeneration indicators and disease progression in metachromatic leukodystrophy using quantitative NMR‐based urinary metabolomics

Metachromatic Leukodystrophy (MLD) is a rare hereditary disease that impacts many organs in the body but primarily affects the nervous system. It leads to the degeneration of the central nervous system (CNS) due to an accumulation of fats called sulfatides. The disease can manifest from two and half years into adulthood. Due to the increased availability of treatments, the need to find more indicators to track the progression of the disease has increased. The study in the article discusses using a urine sample as an indicator. Nuclear magnetic resonance (NMR) spectroscopy is used to diagnose and track various diseases. NMR spectroscopy was used to identify compounds called metabolites. Metabolites are produced by various reactions within the body and can be found in urine samples. The study used this technique for the first time on a large scale, and the results showed that it is a promising evaluation tool for MLD. Upon further study using this technique, many metabolites found were indicators of how severe the disease was and how effective the treatment for patients proved to be. High amounts of specific metabolites found in the urine samples indicated the presence of MLD. The study found that these metabolites would be in lower amounts with effective treatment. Neopterin is another biological indicator that the study used for tracking disease progression. Neopterin is a chemical that can be produced during an immune response. Elevated levels of this chemical in urine samples after treatment with hematopoietic stem cell transplantation (HSCT) indicated that the patient responded well to treatment. Urine samples can provide a comprehensive way to track the progression of MLD before and after treatment. Alongside other indicators, diagnosis can be done more effectively and lead to improved treatments.


Rare Disease

Co-ordinated care for people affected by rare diseases: the CONCORD mixed-methods study

The article discusses how individuals suffering from rare conditions are cared for and how they feel about their care. The co-ordination between patients and accessibility to various care providers or facilities describes co-ordinated care. Examples of this can include the ease of seeing specialists or visiting centres. Different methods were used to examine the approaches to care and evaluate satisfaction with the services provided. The study took place in the UK with people suffering from various rare conditions. The study was approached in six different ways:

  1. A definition and expectations of co-ordinated care was developed.
  2. A way to understand what aspects were lacking in care was established.
  3. A national survey was done to collect information on individual experiences with co-ordinated care.
  4. A study of people’s personal preferences for the co-ordinated care they wished to receive was performed.
  5. The development of a classification system for different types of co-ordinated care was done.
  6. The costs associated with providing co-ordinated care and the mental, physical, and financial consequences of poor care were studied.

The study revealed a lack of satisfaction with the co-ordinated care provided overall. Most patients, carers, and healthcare professionals expressed that they felt access to care co-ordinators, specialist centres, and care plans were inadequate and could be improved. The development of the classification system for different types of care available means that care for rare conditions can be better. Even though co-ordinated care seems to be lacking in many aspects, this development allows for improved experiences suited for an individual’s needs.



Please be aware these summaries are produced voluntarily by Biomedical Science students and are their interpretations of the information and findings. Alex TLC assumes no responsibility or liability for any errors or omissions in the content of these summaries. The information contained in the research summaries is provided on an “as is” basis with no guarantees of completeness, accuracy, usefulness, or timeliness.

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Alex - The Leukodystrophy Charity