Nine participants (five males, four females) were assessed at ages 6 years 2 months to 20 years of age; five out of the nine probands were offspring of consanguineous families of Pakistani origin. Of the remaining four, two were siblings of Afro-Caribbean origin, one Iranian and one adopted (ethnicity unknown). Detailed individual case histories are below. A summary of the participants' clinical features, as well as their KCNJ10 mutation status is summarized in Table 1. A video demonstrating the movement disorder in one patient (5-2) is provided in the online supplementary material.
Individual case histories
The family of patient 1-1 is of Pakistani heritage. This female was born at term after an unremarkable pregnancy by spontaneous vaginal delivery with a birthweight of 3.4kg. She fed and grew well for the first month of life, but then developed irritability, poor feeding, constipation, and failure to thrive, leading to elective admission at 4 months of age. Investigations at that time identified hypokalaemic metabolic alkalosis. Potassium supplementation (8mmol/kg/d) accompanied by indometacin (2mg/kg/d) administration, as well as nasogastric tube feeding, resulted in good weight gain. Hypomagnesaemia with renal magnesium wasting was first noted at 3 years of age.
The first so-called short generalized tonic–clonic seizure (GTCS) was noted at 4 months of age, during the child's first admission to hospital. She experienced multiple GTCS (as recorded) during this hospital stay, which were treated with diazepam, phenytoin, and eventually carbamazepine, which achieved good subsequent seizure control. Surface electroencephalogram (EEG) at 5 months of age was reported as showing spikes and sharp waves localizing to the vertex. She was weaned from carbamazepine at 7 years of age with no seizure recurrence. However, nocturnal events subsequently occurred, and it remains unclear whether these were epileptic in origin. Video-EEG telemetry at 16 years documented three stereotypical events with no preceding EEG changes. The working diagnosis is frontal lobe seizures.
Developmental delay was apparent from the end of her first year: she sat unsupported at 1 year and walked independently at 2 years of age. Moreover, ataxia became apparent with a broad-based gait and intention tremor. At 9 years of age a trial of acetazolamide was given in an attempt to improve the ataxia, but she developed severe headaches and this medication was discontinued. She attends a school for pupils with special needs.
At 5 years of age, she was noted to have hearing problems and was subsequently diagnosed with a sensorineural hearing impairment for which she has been fitted with hearing aids. To date, yearly audiograms show no definite change in the hearing impairment.
At 16 years this patient reveals an ataxic wide-based gait with no apparent truncal ataxia. There is evidence of past-pointing, indicating cerebellar dysfunction. She has bilateral brisk lower limb reflexes with extensor plantar responses and mild facial dystonia, but normal tone elsewhere.
Patient 1-2 (distant cousin of patient 1-1 and sibling of patient 1-3 and patient 1-4)
Patient 1-2 was born at term after an uncomplicated pregnancy with a birthweight of 3.5kg. He first presented at 4 months with an apparent GTCS on awakening, lasting 3 to 4 minutes. Treatment with phenytoin was started at 4 months of age, but he continued to experience GTCS. His antiepileptic medication was changed to valproate at 10 months of age, as he was believed to have developed ‘worsening tremors’ from phenytoin. However, his seizures persisted, lasting 3 to 4 minutes and occurring, on average, twice a month. He spontaneously became seizure free between the ages of 4 years and 7 years 6 months. He was weaned from valproate at 7 years 6 months of age and seizures recurred, but were now of a focal nature, involving staring episodes lasting up to 1.5 minutes, occurring two or three times per day, with skin colour change. There have been no GTCS since 4 years of age, but his focal seizures persist. At his last examination, at 10 years of age, he was being treated with lamotrigine and valproate, with the frequency of his focal seizures being unchanged.
Mild hypomagnesaemia at 0.63mmol/L was noted at initial presentation, at which time he showed failure to thrive. Hypokalaemia was first noted at 11 months of age, but attributed to a concurrent gastrointestinal illness. At 3 years of age he presented again with an intercurrent illness; hypokalaemia (2.2mmol/L) and hypomagnesaemia (0.54mmol/L) led to suspicion of a tubulopathy and oral electrolyte supplementation was instituted.
Neurodevelopment had been delayed from the outset: he first sat unsupported at 2 years of age and walked with support at 4 years of age. He has never gained full independent walking. There has been no deterioration of skills acquired, and there is a very slow but progressive improvement in attempting to walk unaided. He was noted to have a coarse tremor from an early age that becomes more apparent when he performs any motor task. He spoke his first meaningful words at 2 years of age, making two-word sentences at 4 years of age. He has slurring of speech with an explosive tone. He attends a mainstream school with support but is currently not achieving. He has moderate learning difficulties, with evolving behavioural difficulties.
He was not recognized to have a hearing impairment. At the age of 9 years, a formal audiological assessment was attempted, but was unsuccessful owing to impacted cerumen and his motoric and behavioural difficulties.
At 9 years of age, this patient exhibits cerebellar signs, with broad-based gait, intention tremor, titubation, dysdiadochokinesia, and dysmetria. He has no nystagmus. His reflexes are normal, with normal tone and no ankle clonus, and flexor plantar response. He has normal sensation, position, and vibration sense, with no skeletal abnormalities.
This female was born at term after an uncomplicated pregnancy with a birthweight of 3.1kg. She first presented at 4 months of age with GTCS occurring in the early hours of the morning. Biochemical testing at that time revealed mild hypomagnesaemia (0.62mmol/L), but other parameters were normal. Treatment with valproate was commenced immediately because of previous experience with the older sibling (patient 1-2), with good seizure control. She has been seizure free from 4 months of age and she continues to be treated with valproate. The parents noted a coarse tremor from an early age with unsteadiness while attempting any activity. She started walking with hands held at 4 years and has recently started taking a few steps unaided. She has difficulties with fine motor control as a result of tremor, and often uses one hand to support the other while eating or drawing. She spoke her first meaningful words at 1 year 6 months of age and has been making full sentences since 6 years of age. Her speech is slurred with some scanning dysarthria. She attends a mainstream school, where she has demonstrated mild learning difficulties but no behavioural problems.
She was not recognized to have a hearing problem, but audiological testing at the age of 6 years revealed high-frequency hearing loss with absent otoacoustic emissions.
At 6 years of age, she has cerebellar signs, which include gait ataxia, peripheral ataxia with dysdiadochokinesia, dysmetria, and titubation. Her reflexes are exaggerated with ankle clonus but flexor plantar response. She has everted and plantar-flexed feet, but no pes cavus or scoliosis. There is no nystagmus with normal vision and extraocular movements.
This female is the youngest of three siblings (patients 1-2, 1-3). She first presented at 4 months of age with apparent GTCS occurring during sleep. Since then, she has received valproate, as did her sister, with complete seizure control. Electrolytes at presentation were normal, with borderline low potassium (3.8mmol/L) and magnesium (0.73mmol/L) levels. Hypomagnesaemia has been noted intermittently since 10 months of age.
An intention tremor was noted from a very early age. She has truncal ataxia but she seems to be less affected than her other two siblings. She has been walking independently since 3 years 6 months of age. Her gait is broad based, but she is the most confident of her siblings, and has shown gradual developmental progress. Her first meaningful words were at 1 year of age. She is speaking full sentences at present but with slurring of speech and an explosive tone. She attends a mainstream school.
Like her siblings, a hearing problem was not recognized, but audiological testing at the age 4 years revealed high-frequency hearing loss with absent otoacoustic emissions.
On examination at 4 years of age, she has a broad-based gait with tremors, head titubation, dysmetria, and dysdiadochokinesia. Her reflexes are normal, she has no ankle clonus, and she has a flexor plantar response. She has no nystagmus. Audiological testing revealed mild sensorineural impairment.
This male of Pakistani heritage, reviewed at 16 years, is the youngest of three siblings, the older two being fit and well. The family migrated to the UK when he was 9 years old and there are very limited medical records available from before this time. He was born in Pakistan at term after an unremarkable pregnancy with a birthweight of 3.1kg.
The family first lived in the United Arab Emirates, where he presented at 5 months of age with a seizure that occurred from sleep, involving stiffening of arms with facial twitching, and loss of consciousness lasting 5 minutes. Phenobarbital treatment was commenced for seizure control, and was replaced with valproate at 6 months. Subsequently, he developed further apparent GTCS at 9 months of age, lasting 20 minutes. However, he remained seizure free from 9 months to 12 years of age and was weaned from valproate at 4 years. At 12 years of age, he developed a tonic–clonic seizure (TCS) from sleep with left-sided predominance including left-sided facial twitching, lasting 20 minutes. Valproate was recommenced. He currently experiences two types of seizures; first, two or three daily episodes of behavioural arrest associated with lip smacking and loss of awareness, lasting up to 2 minutes and suggestive of focal seizures; second, TCS which occur once every 6 months with a tendency to be prolonged, and on two occasions resulted in intensive care admissions for status epilepticus. Both seizure types have continued despite treatment with phenytoin and valproate.
He was hospitalized at 2 years of age with a 4-day history of fever and vomiting. On admission, serum sodium and potassium levels were 121mmol/L and 1.1mmol/L respectively, leading to a diagnosis of a tubulopathy. He was prescribed potassium supplements, indometacin, and spironolactone.
Over time, an unstable broad-based gait with frequent falls has manifested. On examination he has an intention tremor, dysdiadochokinesia, and dysmetria. He has exaggerated lower limb reflexes, with an ankle clonus of 8 to 10 beats and extensor plantars. There is dystonic posturing of the upper limbs on walking.
His development has been delayed: he crawled at 1 year of age, walked independently at 2 years 6 months of age, and currently falls frequently while walking. He spoke his first meaningful words at 2 years of age, with current slow and slurred speech. He is in special education. EEG at 13 years while on valproate and phenytoin medication showed waves of low amplitude and low frequency. No epileptiform discharges were seen, but a mild excess of slow-wave activity was observed, intermixed in the posterior regions with 2 to 3Hz sharp-wave activity. Repeat EEG at 16 years was normal.
He was suspected of having a hearing problem at the age of 15 years. Subsequent audiological testing revealed sensorineural hearing loss.
This male is of Iranian heritage and his first reported possible seizure occurred during the neonatal period, with generalized stiffening for less than 20 seconds, with spontaneous resolution. At 2 months, further seizures were reported but no further details are available. Treatment with phenobarbital led to seizure control. Subsequently he continued to have a TCS once every 6 to 12 months, always during sleep, which responded to a weight-adjusted dose of phenobarbital. Phenobarbital treatment was maintained until 7 years of age, when it was replaced with lamotrigine with subsequent seizure control.
At 6 years of age, he presented with vomiting and lethargy associated with a viral illness and was noted to have a potassium level of 2.2mmol/L. Subsequent measurements and 24-hour urine sampling reportedly demonstrated renal potassium loss and a tubulopathy was suspected. The parents state that whenever he had a gastrointestinal illness and low potassium values, he had difficulties in moving. Magnesium losses were noted later.
He learned to walk by 7 years of age with a broad-based gait and ataxia and has not deteriorated. He received regular physiotherapy from 3 until 14 years of age, requiring splints, Pedro boots, insoles, and orthotics. A tremor was first noticed at 3 years 6 months of age, this being worse in the morning. He was noted to frequently spill from a cup, and is not able to use a fork at present. He can use zippers, but is unable to do up buttons. He uses a computer to aid his writing skills.
Speech was slurred and slow from an early age and is, at present, explosive. He spoke his first word at 3 years, and at 16 years has a total of 30 spoken words. He has received regular speech therapy throughout his school years.
His parents noted that he did not respond to noises from as early as 1 to 2 years of age, and a formal hearing test at 5 years revealed sensorineural deafness requiring hearing aids. Examination showed ataxia with past-pointing and dysdiadochokinesia; he has generalized increased tone with brisk deep tendon jerks and extensor plantar response.
This male presented aged 2 months with generalized stiffening of the whole body, occurring on awakening. He was adopted as an infant and family history and ethnicity are unclear, as are further details of his early seizure history. He was extensively investigated at 18 months of age and was treated with carbamazepine, which was later replaced with lamotrigine. He continues to have apparent GTCS requiring occasional hospitalization. At 5 years, biochemical investigations revealed a hypokalaemic, hypochloraemic metabolic alkalosis. He was noted to have developmental delay at 2 years 6 months of age, with evidence of ataxia. He achieved walking with the aid of a walking frame. Since the age of 11 years, he has had difficulties supporting his weight and has been using a wheelchair. He had speech delay; sensorineural deafness was detected at age 2 years 6 months necessitating a hearing aid. He is currently able to speak in short simple sentences. No formal speech assessments have been performed. He has been in special education throughout his school years and at 20 years of age lives in a residential college with the aim of acquiring independence skills.
At 20 years of age, he exhibits past-pointing and dysdiadochokinesia with a scanning dysarthric speech. His deep tendon reflexes are present, but not exaggerated. There is a suggestion of dystonic posturing of the fingers when stressed.
The older of two siblings of Afro-Caribbean origin, this female presented at 3 months of age with a reported GTCS. Treatment with valproate was initiated. Seizures were not considered problematic, and she remained seizure free from 4 to 8 years of age. On an attempted wean from valproate, she was troubled by frequent TCS as well as non-convulsive status epilepticus. Control was not regained on reintroduction of valproate, but she became, and remains, seizure free on lamotrigine.
She was not suspected of having a hearing problem, but when screened at the age of 15 years, after her younger brother (patient 5-2) was diagnosed with hearing loss, she was also found to have high-frequency hearing loss.
Electrolytes were first measured at the age of 18 years and revealed hypokalaemic alkalosis and hypomagnesaemia.
She was noted to have increased tone and unsteadiness from infancy. She did attain independent walking at 17 months; however, with the deterioration in seizure control at 8 years she lost mobility and this has not been regained. Her gait shows elements of ataxia; she has intention tremor, dysmetria, and dysdiadochokinesia. There is also apparent dystonia with bradykinesia. There is increased tone in the lower limbs, and no clear clonus, but there are extensor plantar responses. She has a scoliosis. She also has global cognitive difficulties, with the gap widening between her and her peers over the years (18y of age at last review); however, there has been no period of loss of cognitive skills.
This male is the younger brother of patient 5-1. He experienced onset of seizures at 6 months with a self-limiting GTCS. He subsequently had three afebrile seizures at 9 months. He then had no further seizures until 4 years of age, when he developed left focal seizures. These responded to lamotrigine after failed trials of valproate and levetiracetam.
Plasma electrolytes were first checked at initial presentation and included a normal plasma potassium value of 4.4mmol/L. At the age of 5 years, plasma potassium was borderline low at 3.8mmol/L. Magnesium was not tested on either occasion. At 10 years of age he has hypokalaemia (3.3mmol/L), but normal plasma magnesium (0.74mmol/L).
His hearing was first tested at the age of 4 years and revealed sensorineural deafness for which he was fitted with hearing aids.
He began to walk late: at 2 years of age. At the age of 10 years he has an ataxic gait but is able to run. He has intention tremor and dysmetria. His speech also has a cerebellar quality. Muscular tone is symmetrically increased but there is no clonus and flexor plantar response. He is cognitively behind his peers, but making progress.
Neurological development and motor disorder
All children had evidence of early motor delay in their history. Two children (patient 1-2 and patient 4) have never achieved independent walking as a result of ataxia. Age at walking in others ranged from 17 months to 7 years. All have been unsteady to a variable degree with frequent falls from the onset of walking, suggesting ataxia from the outset, with only two patients (patient 5-1 and patient 5-2) reporting a history of steady deterioration. Patient 5-1 walked at 17 months, but this was lost after a prolonged seizure at 8 years. All children were reviewed at a single point in time rather than on serial examinations. However, even within the same family, there is a degree of phenotypic variability, with no obvious relationship between severity of motor impairment and age. In family 1, the three siblings (patient 1-2, patient 1-3, and patient 1-4) were reviewed at 9 years, 6 years, and 4 years. The middle child walked at 6 years and retained the skill, whereas the oldest child has never walked and the youngest achieved independent walking at 2 years.
All the patients who are ambulant walk with a broad-based ataxic gait. All show evidence of dysmetria, dysdiadochokinesia, and intention tremor. One has scoliosis. All have brisk deep tendon jerks, but all except two (patient 13 and patient 2) show no evidence of clonus. There is the suggestion that tone increases with age, with dystonic posturing more evident in the older children.
Detailed neuropsychological assessments have not been carried out, but all children have shown a degree of cognitive delay since the first year of life, with all demonstrating mild to moderate learning difficulties at clinical review. All have shown steady cognitive improvement, albeit slow when compared with their peers. Five have a statement of special educational needs.