6q24–q25 Deletion Syndrome

The chromosome region 6q24–q25 contains a cluster of important genes. Alterations in these genes are linked to a group of rare genetic conditions that affect multiple organ systems, often presenting with severe or complex clinical symptoms. These genes include PEX3, PLAGL1, HYMAI, STX11, EPM2A, GRM1, SYNE1, ARID1B, SERAC1, and RSPH3. Understanding the molecular function of these genes is essential for interpreting the pathophysiology, clinical manifestations, diagnosis, and management of the disorders associated with their dysfunction.

This article provides a gene-by-gene explanation of the relevant conditions, with a focus on mechanisms, symptomatology, diagnostic approaches, and current treatment or management strategies. Where helpful, basic explanations are included for concepts such as imprinting, peroxisomal biology, and chromatin remodeling, in order to make the information accessible without sacrificing accuracy.

Genes and Associated Disorders

PEX3 and Zellweger Spectrum Disorder (ZSD)

PEX3 encodes peroxisomal biogenesis factor 3, a protein that plays a pivotal role in assembling and maintaining the membrane of peroxisomes, which are small intracellular organelles responsible for lipid metabolism and detoxification. Mutations in PEX3 disrupt these processes and lead to Zellweger Spectrum Disorder (ZSD), a group of peroxisomal biogenesis disorders (PBDs).

Peroxisomes perform essential cellular functions, including the breakdown of very long chain fatty acids and the detoxification of harmful compounds. The PEX3 protein acts as a docking factor for PEX19, enabling the transport of proteins to the peroxisomal membrane. This process is a critical step before matrix proteins are transported into the peroxisome.

Clinical Presentation

ZSD encompasses a spectrum from severe neonatal presentations, historically classified as Zellweger Syndrome (ZWS), to intermediate and milder forms, previously described as neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD). These are now understood as a clinical continuum.

Severe ZSD often presents immediately after birth with profound hypotonia, feeding difficulties, seizures, and distinctive craniofacial features. Brain malformations, cystic kidneys, punctate calcifications in long bones, and liver dysfunction are common. In these severe cases, affected infants rarely survive beyond the first year of life due to multiorgan failure.

Intermediate and mild forms present later and progress more slowly. Patients may exhibit sensorineural hearing loss, progressive visual impairment due to retinal dystrophy, peripheral neuropathy, liver disease, adrenal insufficiency, and variable cognitive function. Some mildly affected individuals have normal intellectual development but may still develop subtle skeletal abnormalities, such as reduced bone mineral density or enamel hypoplasia, particularly affecting second molars.

Diagnosis and Management

Diagnosis combines clinical findings, biochemical markers of peroxisomal dysfunction, and genetic confirmation of pathogenic variants in PEX3 or one of the other 13 known ZSD-associated genes. Management is supportive and includes nutritional support (including gastrostomy where required), anti-seizure medication, visual and auditory aids, bile acid supplementation, and physiotherapy. Genetic counseling is recommended due to the autosomal recessive inheritance pattern, with a 25% recurrence risk for siblings.

In Japan, ZSD has been reported in approximately 1 per 500,000 live births, a lower frequency than in some European populations due to differences in the prevalence of specific mutations.

PLAGL1, HYMAI, and 6q24-Related Transient Neonatal Diabetes Mellitus (6q24-TNDM)

Alterations in PLAGL1 and HYMAI within the 6q24 locus are responsible for 6q24-related transient neonatal diabetes mellitus (6q24-TNDM). These genes are imprinted, meaning that only the paternal copy is normally expressed while the maternal copy is silenced by DNA methylation. Disruption of this imprinting process causes overexpression of the paternal allele, leading to abnormal glucose regulation in the neonatal period.

PLAGL1 encodes a zinc finger protein that functions as a transcription factor, regulating pathways such as those involving the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor. HYMAI produces a non-coding RNA that is also paternally expressed, and its biological role, while not fully understood, appears to act in concert with PLAGL1.

Mechanisms of Disease

Three main genetic and epigenetic mechanisms underlie 6q24-TNDM:

• Paternal uniparental disomy of chromosome 6 (UPD6), where both copies of chromosome 6 are inherited from the father
  
• Paternal duplication of the 6q24 region
  
• Hypomethylation of the maternal allele of PLAGL1
  

These mechanisms converge on overexpression of PLAGL1 and HYMAI. Broader imprinting defects, termed multi-locus imprinting disturbance (MLID), may result in more complex phenotypes, including hypotonia, congenital heart disease, epilepsy, and renal malformations.

Clinical Presentation

The condition typically presents within the first month of life with intrauterine growth restriction, hyperglycemia, dehydration, and poor weight gain. Hyperglycemia often resolves spontaneously within three months, but diabetes can recur during adolescence, adulthood, or pregnancy.

Diagnosis and Management

Diagnosis relies on methylation-specific genetic testing, complemented by further molecular studies to clarify the mechanism and provide accurate genetic counseling. Immediate management focuses on hydration and insulin therapy to correct hyperglycemia. Long-term follow-up is essential to monitor for recurrence, at which point management strategies may include diet modification, oral hypoglycemics, or insulin therapy depending on severity.

STX11 and Familial Hemophagocytic Lymphohistiocytosis Type 4 (FHL4)

STX11 encodes syntaxin-11, a protein critical for intracellular trafficking between late endosomes and the trans-Golgi network. Mutations in STX11 cause familial hemophagocytic lymphohistiocytosis type 4 (FHL4), a rare autosomal recessive immune dysregulation syndrome.

Pathophysiology

Loss of syntaxin-11 function impairs the release of cytotoxic granules by natural killer (NK) cells and cytotoxic T lymphocytes, leading to a profound defect in immune regulation. This dysfunction triggers an uncontrolled hyperinflammatory state, known as hypercytokinemia, and infiltration of activated immune cells into multiple organs including the liver, spleen, bone marrow, and central nervous system.

Clinical Presentation

FHL4 typically presents in early infancy or childhood with persistent high fever, hepatosplenomegaly, cytopenia, and often progressive neurological symptoms such as seizures, hypotonia, or ataxia. Rarely, the condition presents in adolescence or adulthood.

Diagnosis and Treatment

Diagnosis combines clinical criteria, laboratory markers of inflammation, and genetic confirmation of biallelic pathogenic variants in STX11. Untreated, FHL4 is almost universally fatal within weeks to months due to multiorgan failure or severe infection. Treatment follows standard HLH protocols such as HLH-94 or HLH-2004, which combine chemotherapy and immunosuppression, followed by allogeneic hematopoietic stem cell transplantation (HSCT). Novel therapies, including interferon gamma blockade with emapalumab, are expanding the therapeutic landscape. Genetic counseling is essential, given the autosomal recessive inheritance pattern with a 25% recurrence risk for siblings.

EPM2A and Progressive Myoclonus Epilepsy, Lafora Type

Mutations in the EPM2A gene, located at 6q24.3, cause progressive myoclonus epilepsy, Lafora type, commonly referred to as Lafora disease. The EPM2A gene encodes laforin, a dual-specificity phosphatase that regulates glycogen metabolism. Laforin prevents abnormal phosphorylation of glycogen and promotes the degradation of proteins that could interfere with glycogen metabolism through interactions with the ubiquitin-proteasome system, particularly with the E3 ubiquitin ligase known as NHLRC1 (also called malin).

When laforin function is lost due to pathogenic variants, glycogen molecules become abnormally phosphorylated and aggregate into insoluble inclusions called Lafora bodies. These accumulate in neurons and other tissues, progressively damaging the nervous system.

Clinical Presentation

Lafora disease typically begins between ages 8 and 18, often during adolescence. The earliest signs include myoclonic jerks, generalized seizures, and visual disturbances such as photopsia or visual hallucinations. Over time, seizures become frequent and resistant to treatment. Neurological decline is steady, with progressive cognitive impairment, dysarthria, ataxia, and eventually complete loss of ambulation. Patients often develop dementia and, within 10 years of symptom onset, most succumb to complications such as status epilepticus or aspiration pneumonia.

Characteristic seizure types include occipital seizures leading to temporary visual loss or visual hallucinations, generalized tonic-clonic seizures, focal seizures with impaired awareness, and atonic seizures. Neurological symptoms progress alongside psychiatric instability and severe functional decline, eventually leading to a vegetative state.

Diagnosis and Management

Diagnosis is based on clinical presentation, electroencephalographic findings, and confirmatory genetic testing for EPM2A or NHLRC1 mutations. In some cases, skin biopsy is used to detect Lafora bodies in sweat glands, although molecular testing is now the preferred method.

There is currently no curative treatment. Management is symptomatic and focuses on seizure control, using agents such as valproate and benzodiazepines, though seizures often remain refractory as the disease progresses. Supportive care includes nutritional support, physiotherapy, and psychological support for patients and families. In advanced stages, gastrostomy may be needed to reduce the risk of aspiration.

Globally, Lafora disease is estimated to affect approximately four individuals per million. Prevalence is higher in populations where consanguinity is more common, such as in the Mediterranean, India, and the Middle East, while some regions, such as Finland, report no cases. Research is ongoing to develop disease-modifying therapies, but current care remains supportive and multidisciplinary.

GRM1 and Autosomal Recessive Spinocerebellar Ataxia Type 13 (SCAR13)

Pathogenic variants in the GRM1 gene, which encodes the metabotropic glutamate receptor 1 (mGluR1), cause autosomal recessive spinocerebellar ataxia type 13 (SCAR13). This receptor is expressed at high levels in Purkinje cells in the cerebellum, where it regulates synaptic plasticity, neuronal signaling, and motor learning. Alteration of this receptor disrupts cerebellar development and function, leading to motor and cognitive symptoms.

Clinical Presentation

SCAR13 usually presents in infancy or early childhood. Common clinical features include delayed motor and cognitive development, hypotonia, spasticity, hyperreflexia, and ataxia. Speech delay is often severe, with some individuals remaining non-verbal. Other frequent symptoms include nystagmus, seizures, and peripheral neuropathy. Brain imaging typically shows cerebellar atrophy and may reveal ventricular enlargement.

In one reported case, an eight-year-old patient exhibited profound motor delays, an inability to walk independently, and no language development. Genetic testing revealed compound heterozygous variants in GRM1, confirming the diagnosis.

Diagnosis and Management

Diagnosis is based on clinical findings, neuroimaging, and molecular testing for GRM1 mutations. There is no specific treatment. Management focuses on supportive therapies to maintain function and improve quality of life. This includes physiotherapy to address motor dysfunction, occupational therapy to assist with daily activities, and speech therapy to optimize communication. Assistive devices such as walkers or communication devices are often required. Pharmacological options such as baclofen or tizanidine may be used to reduce muscle tone and spasticity, while psychological and environmental support are essential to reduce complications and promote safety.

SYNE1 and SYNE1 Deficiency

SYNE1 encodes nesprin-1, a structural protein that connects the nuclear envelope to the cytoskeleton, maintaining cellular architecture and signaling integrity. Mutations in this gene cause a spectrum of disorders collectively known as SYNE1 deficiency.

Clinical Spectrum

The clinical presentation is highly variable. The most common phenotype is autosomal recessive cerebellar ataxia type 8 (SCAR8), characterized by slowly progressive cerebellar ataxia, dysarthria, and oculomotor abnormalities. Many individuals with SCAR8 also develop signs of upper motor neuron involvement, such as spasticity and hyperreflexia, or lower motor neuron signs, including muscle atrophy and fasciculations. Cognitive impairment, particularly involving executive function and visuospatial skills, can occur.

Other phenotypes include Emery-Dreifuss muscular dystrophy type 4 (EDMD4), which presents with early contractures of the elbows, Achilles tendons, and spine, along with progressive skeletal muscle weakness and cardiomyopathy with conduction abnormalities. A third phenotype, arthrogryposis multiplex congenita type 3 (AMC3), is characterized by reduced fetal movement, joint contractures at birth, hypotonia, and severe developmental delays. Infants with AMC3 often present as “floppy infants” with multiple contractures.

Diagnosis and Management

Diagnosis is based on clinical presentation and confirmed through molecular testing for SYNE1 variants. The inheritance pattern is autosomal recessive. Carrier parents have a 25 percent risk of recurrence in each pregnancy, with a 50 percent chance that a sibling will be a carrier.

There is no disease-modifying therapy. Management is supportive and requires multidisciplinary care involving neurology, physiotherapy, occupational therapy, speech therapy, orthopedics, cardiology, and respiratory specialists. Early interventions focus on maintaining mobility, preventing contractures, and addressing communication and respiratory issues. For patients with cardiac involvement, regular monitoring and early treatment of conduction abnormalities are critical. The disorder was first identified in French Canadian populations but is now recognized worldwide.

ARID1B and ARID1B-Related Disorders, Including Coffin-Siris Syndrome

Pathogenic variants in the ARID1B gene, located at 6q25.3, lead to ARID1B-related disorders, which encompass a spectrum of neurodevelopmental syndromes. The most well-known phenotype within this spectrum is Coffin-Siris syndrome type 1 (CSS1). The ARID1B gene encodes a key subunit of the SWI/SNF chromatin remodeling complex, which regulates gene expression by altering the structure of chromatin during development. This process is essential for proper differentiation of stem cells into neuronal cells.

Clinical Presentation

Individuals with ARID1B-related disorders frequently present with developmental delay and intellectual disability of variable severity. Hallmark physical features include hypoplasia or aplasia of the fifth digit nails or distal phalanges, coarse facial features such as a broad nasal bridge and thick lips, hypotonia, and hypertrichosis, particularly on the face and back. Additional findings may include congenital anomalies of the heart, gastrointestinal tract, kidneys, or central nervous system, as well as feeding difficulties, short stature, visual problems including myopia or strabismus, hearing impairment, and seizures. Behavioral concerns such as attention deficit hyperactivity disorder and autism spectrum features are common.

Diagnosis and Management

Diagnosis is established through clinical assessment and confirmed by molecular genetic testing for ARID1B variants. Most cases are caused by de novo mutations, but autosomal dominant inheritance has been reported in familial cases.

Management is individualized and focused on supportive interventions. These include developmental therapies such as speech, occupational, and physical therapy, management of feeding difficulties including possible use of nasogastric or gastrostomy feeding, treatment of seizures, and corrective interventions for visual and auditory impairments. Behavioral therapy and, when indicated, pharmacological treatment are used to address behavioral issues. While longitudinal data are limited, survival into adulthood, and even into the fifth decade of life, has been documented, underscoring the importance of ongoing support and multidisciplinary care.

SERAC1 and 3-Methylglutaconic Aciduria with Deafness, Encephalopathy, and Leigh-Like Syndrome (MEGDEL)

Mutations in the SERAC1 gene, located in the 6q25.3 region, cause 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL). This gene encodes the SERAC1 protein, which is essential for remodeling phosphatidylglycerol, a lipid critical for both mitochondrial function and intracellular cholesterol transport. Deficiency in SERAC1 disrupts mitochondrial energy production and lipid trafficking, leading to the multisystem phenotype observed in affected individuals.

Clinical Presentation

MEGDEL syndrome typically presents in infancy. Early features include hypotonia, poor feeding, and developmental delay. Many infants exhibit transient hepatic dysfunction ranging from mild transaminase elevations to acute liver failure. By the second year of life, sensorineural hearing loss, spasticity, dystonia, and loss of previously acquired developmental skills become evident. Over time, progressive neurological decline leads to severe motor and cognitive impairment, with most children requiring full care for daily activities.

Laboratory testing consistently identifies elevated urinary 3-methylglutaconic acid, a diagnostic marker for the disorder. Brain imaging often reveals cerebral and cerebellar atrophy and basal ganglia lesions similar to those seen in Leigh syndrome. Additional biochemical findings may include elevated blood lactate and alanine and evidence of abnormal cholesterol trafficking in cultured fibroblasts.

Diagnosis and Management

Diagnosis is based on clinical presentation, biochemical testing showing increased urinary organic acids, and confirmatory genetic testing for biallelic SERAC1 variants.

There is no curative treatment. Management is supportive and multidisciplinary, often requiring collaboration among neurologists, geneticists, physiotherapists, dietitians, and speech therapists. Spasticity may respond to oral or intrathecal baclofen. Sialorrhea that compromises respiration can be treated with botulinum toxin injections or surgical interventions targeting the salivary glands. Nutritional support, frequently through gastrostomy feeding, helps maintain growth and reduce the risk of aspiration pneumonia.

The clinical spectrum varies widely, ranging from severe infantile presentations to milder cases that may reach adolescence or adulthood. The estimated prevalence of MEGDEL syndrome is approximately 0.09 per 100,000 individuals, highlighting its rarity. Because some features resemble cerebral palsy, particularly in cases without obvious MRI findings, urinary organic acid analysis is recommended when the diagnosis is uncertain.

RSPH3 and Primary Ciliary Dyskinesia Type 32 (CILD32)

Mutations in the RSPH3 gene, located at 6q25.3, result in primary ciliary dyskinesia type 32 (CILD32). The RSPH3 gene encodes radial spoke head protein 3, a structural protein critical for the proper assembly and function of motile cilia. RSPH3 also acts as a scaffold protein anchoring cAMP-dependent protein kinase (PKA) within the ciliary axoneme, facilitating intracellular signaling pathways that regulate ciliary motion.

When this protein is dysfunctional, cilia throughout the body exhibit structural and functional abnormalities, leading to the impaired clearance of mucus and pathogens from the respiratory tract and defects in reproductive function.

Clinical Presentation

CILD32 manifests primarily as a respiratory disease. Affected newborns may present with respiratory distress shortly after birth, often requiring neonatal intensive care. Throughout childhood and adulthood, patients experience recurrent upper and lower respiratory tract infections, chronic sinusitis, and persistent productive cough. Progressive bronchiectasis, detectable through high-resolution computed tomography, is a near-universal feature in adults.

Middle ear disease, including recurrent otitis media, is common and often leads to conductive hearing loss. Progressive hearing impairment may require hearing aids or other auditory support.

Infertility is common in affected males due to impaired motility of sperm flagella. Females may also experience reduced fertility because of impaired ciliary function in the fallopian tubes, which increases the risk of ectopic pregnancy.

Unlike other forms of primary ciliary dyskinesia, situs abnormalities such as situs inversus have not been reported in association with RSPH3 variants.

Diagnosis and Management

Diagnosis is based on a combination of clinical features, nasal nitric oxide testing (which typically shows reduced levels), ultrastructural analysis of cilia by electron microscopy, and molecular genetic testing to confirm RSPH3 mutations. Some patients may not show identifiable mutations with current testing, necessitating further advanced genetic analysis.

There is no curative therapy for CILD32. Management is aimed at minimizing symptoms and preventing disease progression. Airway clearance techniques such as chest physiotherapy and postural drainage are cornerstones of care. Prompt antibiotic therapy is used to manage respiratory infections, and vaccination is recommended to prevent respiratory pathogens such as influenza and pneumococcus. Surgical interventions, such as tympanostomy tube placement, may help in managing chronic otitis media. Hearing rehabilitation and speech therapy are often needed in children with hearing loss.

Preventive care is essential to delay the progression of lung damage. This includes avoidance of environmental irritants such as tobacco smoke and air pollution, regular monitoring of pulmonary function, and early detection of bronchiectasis.

Although CILD32 is extremely rare, early diagnosis and consistent management can improve quality of life and preserve lung function in affected individuals.

References

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Footnotes and Technical Clarifications

1. PEX3 and Zellweger Spectrum Disorder
   The subtype of Zellweger spectrum disorder associated with PEX3 variants is also designated as peroxisome biogenesis disorder 10A (PBD10A) in some classifications, in addition to being referred to as peroxisome biogenesis disorder complementation group 12 (PBD-CG12).
   
2. PLAGL1/HYMAI and 6q24-TNDM
   Some cases of hypomethylation at the PLAGL1 promoter are caused by variants in ZFP57, an imprinting regulator that maintains methylation patterns across multiple loci, leading to dysregulated expression of imprinted genes.
   
3. SERAC1 and MEGDEL Syndrome
   In addition to its role in general phosphatidylglycerol remodeling, SERAC1 deficiency specifically reduces levels of phosphatidylglycerol-36:1 and alters the biosynthesis of bis-monoacylglycerol phosphate (BMP), both of which are critical for maintaining mitochondrial membrane integrity and cholesterol transport.
   
4. RSPH3 and Ciliary Structure
   Pathogenic variants in RSPH3 disrupt the motile ciliary 9+2 axonemal architecture, a conserved ultrastructural arrangement essential for coordinated ciliary movement and mucociliary clearance.