Barakat-Perenthaler syndrome

Overview

Barakat–Perenthaler syndrome is an extremely rare autosomal recessive genetic disorder associated with severe early-onset epilepsy and global developmental delay. The syndrome was recently described and is characterized by profound neurological impairment from birth. It is caused by mutations in theUFM1 gene, which plays a role in a cellular process known as UFMylation—a type of protein modification important for cell homeostasis, especially in the brain. Due to its recent identification and rarity, much about the condition is still being researched.

Causes

Barakat–Perenthaler syndrome is caused by biallelic (both copies) mutations in theUFM1 genelocated on chromosome 13q13.3. The UFM1 gene encodes a ubiquitin-fold modifier protein involved in UFMylation, a process that regulates protein function and cellular stress responses. Key causes include:

• Homozygous or compound heterozygous mutations in UFM1

• Autosomal recessive inheritance pattern – both parents are typically asymptomatic carriers

• Consanguinity may increase the risk of occurrence in some populations

Symptoms

Barakat–Perenthaler syndrome presents with severe neurological symptoms that begin in the neonatal period:

• Neonatal-onset epilepsy – typically drug-resistant and severe

• Profound developmental delay – with little to no developmental milestones achieved

• Microcephaly – small head circumference at birth or developing postnatally

• Muscle hypotonia – low muscle tone

• Seizures – frequent, difficult to control, and often start within the first days of life

• Brain atrophy and abnormalities seen on MRI

• Possible feeding difficulties and failure to thrive

Diagnosis

Due to its rarity, diagnosis of Barakat–Perenthaler syndrome requires a high index of suspicion and advanced genetic testing:

• Clinical assessment revealing early-onset seizures and developmental stagnation

• EEG showing epileptic encephalopathy patterns

• Brain MRI revealing cerebral atrophy or delayed myelination

• Whole exome sequencing or targeted gene panel to identify pathogenic mutations in the UFM1 gene

• Family history and carrier testing for parents and siblings

Treatment

There is currently no cure for Barakat–Perenthaler syndrome. Treatment is supportive and aimed at symptom management:

• Antiepileptic medications – though seizures are often drug-resistant

• Feeding support – including nutritional supplementation or gastrostomy tube feeding

• Physical and occupational therapy to manage tone and positioning

• Multidisciplinary care involving pediatric neurology, palliative care, nutrition, and physical medicine

• Genetic counseling for affected families

Supportive care may help improve comfort and quality of life, though developmental gains are minimal or absent.

Prognosis

The prognosis for individuals with Barakat–Perenthaler syndrome is poor:

• Severe, intractable epilepsy and neurological dysfunction dominate the clinical course

• Developmental progress is extremely limited

• Life expectancy may be significantly shortened due to uncontrolled seizures and complications

• Palliative-focused care is often appropriate

Research is ongoing, and future discoveries may help clarify the full spectrum and potential interventions for this syndrome.