The 44 patients ranged from 2 to 38 years (). They were followed for an average duration of 3.3 years (range 0–18 years). All but one of the patients were male. The female patient had a clinical phenotype indistinguishable from that of the males.
Medication use at evaluation
All but one patient were receiving allopurinol for control of uric acid. Twelve were receiving medications to alkalinize the urine to promote uric acid solubility. Eleven were taking medications for gastro-oesophageal reflux.
Seven were taking medications to reduce muscle tone (baclofen, dantrolene, paracetamol). Nineteen were taking benzodiazepines to alleviate both increased muscle tone and mood lability (diazepam, clonazepam, alprazolam). Seven were taking dopamine receptor antagonists (risperidone, thioridazine, olanzepine) for control of self-injury and two were taking metaclopramide to promote gastrointestinal motility. Eleven were taking medications for mood stabilization or depression (paroxetine, gabapentin, carbamazepine, clomipramine, sertraline). Though this study was not designed to assess treatment responses, none of these medications was clearly associated with a dramatic improvement of the motor disorder. Motor abnormalities among those taking dopamine receptor antagonists were similar to those who had never taken them.
Presentation and developmental progression
Information concerning presenting signs was available from the histories in 39 patients. All but two first came to medical attention for motor delay (). Motor delay became apparent most often at 3–6 months of age as hypotonia, with failure to sit upright unsupported. Overt involuntary movements most often were noted between 6 and 12 months of age, although abnormal movements sometimes were appreciated by parents or caretakers earlier, or delayed for up to 4 years.
After some evolution during the first few years, the severity of the motor disorder appeared relatively static rather than progressive in most cases. The majority of patients were reviewed more than once over a period of several years, and progression of the motor disorder was not significant beyond 5–6 years of age. The oldest patients did not appear to be more seriously affected than the youngest ones. However, several patients evidenced signs of increasing disability from long-standing abnormal movements. For example, three patients had histories noting objective signs of worsening motor function, such as loss of grasp or ability to stand with assistance, often in a stepwise fashion. Six developed severe scoliosis, and one required a surgical procedure to stabilize the spine.
Only two patients presented first with difficulties attributable to excessive production of uric acid. One presented with lactic acidosis, presumably due to nephrolithiasis with obstruction of urine flow and renal failure. The other presented with orange crystals in the diapers, most probably due to crystalluria combined with microhaematuria. No patient presented with self-injurious behaviours, which consistently emerged later than the other problems, usually between 1 and 8 years of age.
Abnormal movements were relatively minor at rest in all patients, and became most obvious with stress, excitement, anticipation or voluntary movement. The most prominent feature of the motor syndrome in all patients was dystonia (, ). Essentially, all parts of the body were affected. Multidirectional cervical dystonia was universal. Truncal twisting and arching was present in all, particularly with efforts to stand. Dystonia of the upper limbs prevented their use for most tasks such as feeding or grasping in all patients. All regularly used wheelchairs because lower limb dysfunction prevented them from walking or standing unassisted. Oromandibular and lingual dystonia were evident during speaking or eating in most. Several also exhibited blepharospasm, most prominently during ocular testing. Several developed fixed abnormal postures of the hands or feet, and fixed contractures of the hamstring muscles with incomplete extension at the knee were common. Muscle hypertrophy resulting from long-standing dystonia was evident in several patients in the neck and arms.
Fig. 1 Summary of the motor signs in current series of 44 LND patients. The most common signs were extrapyramidal (A), abnormalities of resting tone (B) and pyramidal signs (C). Overlapping hatch marks show patients with overlapping signs. The extensor plantar (more ...)
Severe opisthotonus or truncal arching was observed directly in 11 (25%), and movements compatible with opisthotonus were described frequently in the medical records as severe or prolonged ‘arching’ or ‘backward bending’ of the trunk. Sudden and rapid backward thrusting of the head without concomitant truncal involvement was observed directly in four and described in the records of several others. Such spasms were absent at rest, but emerged when patients attempted to stand or were transferred from the seated to supine position. Severe, sustained truncal arching with dystonic tremor sometimes resembled a generalized epileptic seizure, except that consciousness was preserved and there was no post-ictal depression of consciousness.
Although dystonia was universal and always the most severe extrapyramidal disorder, choreoathetosis was present in 22 (50%) and ballism was observed in 13 (30%). Ballism was most common in the arms, though it occasionally appeared in the legs. These movements were seen almost exclusively with excitement or agitation. Ballism was often triggered by the presence of an object near enough to strike, raising the question of whether this represented impulsive or voluntary acts of aggression. However, the movements otherwise appeared typical of ballism, and their speed and fluidity contrasted with the marked impairment in all other voluntary movements.
Resting muscle tone
When fully relaxed, 40 (91%) patients were considered to have hypotonia (; ). Spasticity was noted in 10 (23%) patients. In six of these the spasticity was limited to the legs, and in three others it was markedly asymmetrical. Rigidity was noted in six (14%), but cogwheeling was not apparent.
Corticospinal tract signs
A total of 23 patients (52%) had pathologically brisk muscle stretch reflexes (). Pathological reflexes were limited to the legs in 17 of these patients, and they were asymmetrical in 5. Clonus was observed in 14 (32%) cases, and in 13 of these cases it was limited to the legs.
Several patients demonstrated an abnormal resting posture of the great toe. In some, the toe was plantar flexed and deviated laterally at the metacarpophalangeal joint in a fixed position above or below the adjacent toe. In others, the toe remained in extension for lengthy periods without plantar stimulation, but eventually returned to a normal position. Plantar stimulation often led to varied responses, with an extensor on some occasions and a flexor on others. These phenomena were considered more characteristic of a striatal toe response than a classic Babinski sign, but distinction between these signs was not attempted.
Dysarthria and dysphagia
Speech was delayed in all patients for whom developmental histories were available. Most began using words by 2–4 years of age. A few were not speaking at much older ages, such as one who was still not using words by age 14 years.
When speech occurred, it was always dysarthric. In all patients, dysarthria was severe enough that speech was difficult to understand without frequent repetition. One was anarthric because of extreme cervical and oromandibular dystonia but communicated effectively with a keyboard. Most communicated using only single words or very short phrases. Speech had the typical characteristics of striatal dysarthria, with slow and irregular enunciation associated with excessive activation of pharyngeal, lingual, and perioral muscles. During casual conversation, a trailing volume was common and sufficiently soft to be considered pathologically hypophonic in 10 (23%) patients, and 2 (4%) of these also exhibited stuttering without obvious jaw dystonia. Spasmodic dysphonia with intermittent breathiness, intermittent strained-strangled quality or phonic breaks was not apparent. None had a high-pitched, nasal or strained-strangled quality suggestive of spastic dysarthria. None displayed poor modulation of tempo or volume suggestive of cerebellar dysarthria.
Chewing and swallowing was laboured in most patients. Many also had gastro-oesophageal reflux with frequent emesis (). Together, these problems were sufficiently severe to require gastrostomy tube in nine (20%) patients.
Respiratory abnormalities were evident in several patients. Two patients had prominent inspiratory stridor without cyanosis or apnoea during examination and another had a history of recurrent ‘noisy breathing’ (). In all three patients, the respiratory problems were noted during wakefulness and not during sleep. Two other patients had frequent episodes of apnoea and cyanosis without stridor, also during wakefulness but not during sleep. Extensive pulmonary evaluations were normal for both, and EEG studies provided no evidence for epilepsy. Two other patients each had at least one episode of cardiopulmonary arrest leading to multiple hospitalizations, and extensive evaluations failed to disclose a cause. One of these patients expired without obvious cause, presumably due to an unwitnessed respiratory event. Another case with no history of cardiopulmonary events expired during sleep with no apparent cause.
Three patients had histories compatible with generalized tonic–clonic epileptic seizures, though none was witnessed by the evaluators, and the possibility of prolonged opisthotonic posturing with dystonic tremor could not be excluded. One case had episodic and briefly sustained upwards or lateral conjugate eye deviation resembling ocular tics. Two cases with a history of neuroleptic use exhibited repetitive orobuccolingual stereotypies typical of tardive dyskinesia. Other tics or stereotypies were absent. None of the patients had evidence for cerebellar dysfunction such as appendicular or axial ataxia or ocular dysmetria. Tremor and myoclonus were absent.