PEHO syndrome

Overview

PEHO syndrome, an acronym for Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy, is a rare neurodegenerative disorder that presents in infancy. First described in Finland, PEHO syndrome is characterized by profound developmental delay, seizures, facial and limb swelling (edema), abnormal brain activity (hypsarrhythmia), and progressive loss of vision due to optic atrophy. It primarily affects the central nervous system and leads to severe neurological impairment. The condition is extremely rare and is considered part of a broader group of early-onset progressive encephalopathies. PEHO-like syndromes have been reported in non-Finnish populations, showing similar but slightly varying clinical features.

Causes

PEHO syndrome is believed to be a genetic disorder inherited in an autosomal recessive manner. This means both parents must carry one copy of the mutated gene for their child to be affected. While the exact gene responsible remains unclear in many cases, mutations in the ZNHIT3 gene have been identified in several Finnish patients. Additionally, some PEHO-like cases have shown mutations in other genes such as KIF1A and CASK, though these may represent related but distinct syndromes. Ongoing research aims to further clarify the genetic basis and molecular pathways involved in this devastating condition.

Symptoms

PEHO syndrome presents shortly after birth or within the first few months of life. The core symptoms and features include:

• Severe hypotonia: Marked muscle weakness and low muscle tone at birth

• Developmental delay: Global delay in cognitive, motor, and social skills with minimal to no developmental progression

• Infantile spasms: Seizures typically presenting as spasms in early infancy, often accompanied by hypsarrhythmia on EEG

• Hypsarrhythmia: A chaotic brain wave pattern seen on electroencephalogram (EEG) associated with epileptic spasms

• Optic atrophy: Progressive degeneration of the optic nerves leading to visual impairment or blindness

• Facial and limb edema: Puffiness or swelling of the face and limbs, often without an identifiable cause

• Microcephaly: A smaller than normal head size that worsens over time due to brain atrophy

• Dysmorphic features: May include a narrow forehead, deep-set eyes, and prominent upper lip

In some cases, additional findings such as cerebellar atrophy, abnormal muscle reflexes, and involuntary movements may be present. The condition is relentlessly progressive, with most affected children showing regression in acquired skills and worsening neurological function over time.

Diagnosis

Diagnosing PEHO syndrome can be challenging and requires careful clinical evaluation along with supportive laboratory and imaging findings. The diagnostic approach includes:

• Clinical evaluation: Recognition of characteristic features including early-onset seizures, developmental delay, optic atrophy, and edema

• Electroencephalogram (EEG): Shows hypsarrhythmia, a chaotic and disorganized brain wave pattern typical of infantile spasms

• Magnetic Resonance Imaging (MRI): Reveals progressive brain atrophy, particularly in the cerebral and cerebellar regions

• Ophthalmologic examination: Confirms optic nerve atrophy

• Genetic testing: May identify mutations in the ZNHIT3 gene or other genes associated with PEHO-like features

• Exclusion of other causes: Rule out metabolic or infectious causes of early-onset encephalopathy and seizures

PEHO is considered a clinical diagnosis supported by neuroimaging and EEG findings. Genetic confirmation, if available, may aid in counseling and recurrence risk assessment.

Treatment

There is currently no cure for PEHO syndrome. Treatment is supportive and aimed at alleviating symptoms, improving comfort, and enhancing quality of life. Management includes:

• Seizure control: Antiepileptic medications such as vigabatrin or ACTH may be used to manage infantile spasms, though seizures are often resistant to treatment

• Physiotherapy and occupational therapy: To maintain joint mobility and prevent contractures, despite limited developmental progress

• Nutritional support: Including feeding assistance and management of gastrointestinal complications

• Visual aids and monitoring: Although vision loss is progressive, early support may help with adaptation

• Management of edema: Generally conservative; diuretics are rarely needed unless associated with other complications

• Multidisciplinary care: Involves neurologists, geneticists, physical therapists, nutritionists, and palliative care specialists

Family support, counseling, and access to specialized care services are essential parts of the treatment plan.

Prognosis

The prognosis for PEHO syndrome is poor. The condition is progressive and leads to profound disability. Most affected children do not achieve meaningful developmental milestones and may become completely dependent on caregivers for all aspects of daily living. Life expectancy is typically limited, with many patients succumbing in early childhood due to complications such as uncontrolled seizures, respiratory infections, or nutritional failure. However, with attentive supportive care, some children may survive into adolescence. Early diagnosis and comprehensive management can help optimize comfort and support families in coping with the challenges posed by this devastating condition.