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Clinical characteristics


Males with CLCN4 related condition

To date the condition is fully penetrant in affected males (27 males are currently known who are affected with an inherited CLCN4 gene change, and 3 with a de novo CLCN4 genetic change).  However the severity of symptoms can vary significantly in a family. The presence of an intractable seizure disorder is usually associated with a more severe phenotype.

The main clinical features are summarised below:

1. Intellectual disability (ID)  present in 100% of affected males. The severity has ranged from borderline (1/30: 3%), to mild (7/30: 23%), moderate 9/30 (30%) and severe/profound (13/30 :43%) Expressive and receptive language is commonly an area of particular concern.

2. Seizure disorder has been diagnosed in 53% of affected males. Seizures have been well controlled in 44% of those with seizures and intractable to polytherapy in 55% of those with seizures. The seizure semiology can vary from infrequent seizures, well controlled with monotherapy to severe infantile-onset intractable epilepsy , even within a family. Reported seizure types include infantile spasms, absence, myoclonic, tonic, complex partial and generalised tonic-clonic. Reported EEG findings included focal spikes, multifocal spikes and generalised background slowing

3. Behavioural issues/mental health disorders (19/30 (63%))

Some males were reported to be of amiable personality with no significant challenging behaviours or mental health concerns, but 63% have been reported to have significant behavioural or mental health issues including  hetero and auto-aggressive behaviour, repetitive autistic or obsessive-compulsive like and hyperactivity. Depressive or anxiety symptoms  have been reported in 24% of males, including one diagnosis of bipolar disorder.

4. Additional neurological symptoms

Infantile hypotonia was reported in 9 males across 7 families. Additional reported neurological signs in childhood have included strabismus (3 males), cortical visual impairment (2 males), gait abnormality (1 male), upper limb choreiform movements (1 male) and evolving upper limb / generalised spasticity in childhood (2 males). Progressive ataxia and/or lower limb spasticity were described after the third decade in 4 males from 2 families. Additional longitudinal data will be required to evaluate how common progressive neurological symptoms are in affected males.

5. Neuroimaging

Abnormalities on neuroimaging/ neuropathology were noted in 8 tested males across 6 families. However, the majority of males have not had neuroimaging: brain MRI was normal in an additional 4 males. White matter abnormalities and cortical atrophy were characteristic: periventricular leukomalacia and/or ventricular dilatation was noted in childhood with additional features of delayed myelination and hypoplastic corpus callosum in early childhood and cortical atrophy and middle and older age.

6. Growth parameters and dysmorphism

Common distinctive features in older male individuals included a long face with straight nose and a prominent pointed chin, that becomes more ‘squared off’ with age, and relatively flat midface. Facial features are not so characteristic in younger males. Growth parameters are generally within the normal range, however many older individuals have a lean body habitus and both micro and macrocephaly has been noted.

7. Additional features

No consistent pattern of extra-neurocognitive symptoms have been reported, and  many features are commonly seen in children with ID of other causes: including gastrooesophageal reflux and early feeding difficulties. Scoliosis, cryptorchidism and inguinal hernia have been occasionally reported.


Heterozygous females with familial variants (18 individuals )

The phenotype in females with familial CLCN4 variants has been reported to be strikingly variable, ranging from apparently completely unaffected to severely affected, even within a family. Two obligate female carriers from one family noted to have subtle learning/behavioural difficulties.  One heterozygous female from another family had severe ID, intractable seizure disorder, cerebral atrophy and progressive spasticity and ataxia.  No alternative diagnosis has been found in this severely affected female.


Heterozygous females with de novo variants (5 individuals )

The phenotype in the 5 reported heterozygous females with de novo variants has been found to be more severe and consistent with the phenotype in hemizygous males.

1. intellectual disability

One affected female had borderline, 2 had moderate and 2 had severe-profound intellectual disability; again language development, especially expressive language, has been noted as  an area of particular concern.

2. Seizure disorder

Two girls with de novo variants have seizure disorders of varying severity.

3. Behavioural/ mental health conditions

Two girls have self-injurious behaviours, one was assessed as emotionally reactive; the other two girls had no significant behavioural issues.

4. Neurological symptoms

Three girls had infantile hypotonia and one developed mildly increased peripheral tone with brisk patellar reflexes.

5. Neuroimaging changes

Four girls had neuroimaging by MRI: reported as normal for 2 ; there was subtle neuropathology in the other 2 with diffuse cortical and corpus callosum hypoplasia in one and persistently enlarged third ventricles and T2/FLAIR subcortical hyperintensities in the other.

6. Growth parameters/dysmorphism

Two of the girls with de novo variants have microcephaly: other growth parameters have been found to be within normal limits. Subtle dysmorphic features have been noted in 3 girls including down-sloping palpebral fissures with depressed nasal bridge.

6. Additional features

Two of the five girls had significant feeding difficulties in infancy; one had congenital diaphragmatic hernia (CDH) and bilateral hip dysplasia and one had scoliosis. However the pathogenicity of the CLCN4 variant reported in the individual with CDH is uncertain, and it is not definite that the CLCN4 variant is causal of the CDH.