2. Patients and Methods
Conflicts of Interest
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|First Symptoms||Comorbidities||Predominant Challenging Situation with Special View Regarding Medication|
|Change in muscle tone, frequent falls and increasing gait disorder||Epilepsy||Clinical examination (CE): bradykinetic motor-phenotype with increased muscle-tone, rigidity and spastic component, hypokinesia, cognitive decline and dystrophy.|
Further diagnostics (FD): comprehensive genetic diagnostics with chromosome analysis, analysis of array-based comparative genomic hybridization, analysis of methyl-CPG-binding-protein 2 gene. MRI: Narrowing of the caudate nucleus on both sides and subsequent gene testing with HD diagnosis.
Treatment attempts (TA): initially L-dopa/carbidopa attempt because of a suspected tyrosine hydroxylase deficiency.
Low-dosed pramipexole retard (bradykinesia) in combination with quetiapine (due to dopa-induced hallucination) lead to an improvement of movement disorder. Clobazam (anxiety- reducing and sleep- inducing) reduced ongoing sleep-disorder and had a positive effect on dystonia and the increased muscle tonus. Levetiracetam used for the treatment of epilepsy.
Course of disease (CD): use of dronabinol for palliative medical care with positive effects on muscle tonus, dystonia and body mass index (BMI).
|Problems in school, pronounced tremor with medium amplitude, gross and fine motoric function||Anamnesis (A): early genetic testing because of positive family history, but retrospective symptoms already exist for the past 4 years.|
CE: initially hypomimia, lack of arm swinging, cognitive deficits.
Socio-medical aspects (SM): re-educated after diagnosis in a special school, which helped enormously. After depression with several suicidal attempts, irritable behavior, lack of impulsion, apathy, schooling no longer possible. Long-term psychiatric ward.
FD: electroencephalography (EEG): isolated bi-frontal sharp-wave-like activity and typical epilepsy potentials but no seizures observed while treatment with valproate (for stabilizing irritability).
TA: pramipexole (treatment of bradykinesia), venlafaxine (antidepressant), valproate retard, lithium (antidepressant and because of suicidal intent), quetiapine (antipsychotic). In adulthood, worsening of dystonia and spasticity (tiazidine initiated), swallowing and because of improved mood and absence of suicidal tendencies lithium stopped.
|Problems in school, depression, tremor||A/CE: stressful family situation, father died due to suicide, sister died due to HD. Unspecific symptoms reported (depression, due to HD or family situation?). No genetic testing during the first visit. An additional tremor three months later indicated the genetic testing. |
FD: diagnostic of cranial MRI, awake, sleep EEG, electrocardiography (ECG) inconspicuous.
SM: arrangement with school, compensations for disadvantages helped remaining in class.
TA: psychotherapy, occupational therapy but no additional pharmacological therapy necessary at the present.
CD: mild bradykinesia in finger tapping without negatively influencing everyday life.
|Progressive motoric dysfunction, speech problems and problems in school||Epilepsy Severe expressive speech disorder||A: postnatal difficulties in thriving and swallowing.|
CE: bradykinesia in addition to hyperkinetic restlessness at night.
FD: cranial MRI (second year of life) revealed a reduction of brain volume (retrospective evaluated as physiological expansion of the external cerebrospinal fluid spaces in infancy).
TA: pramipexole retard (improved bradykinesia), valproate retard (positive influence on irritability), quetiapine (reduction of irritability and hallucinations), L-dopa/carbidopa (positive influence on rigidity)
CD: severe swallowing disorder, but percutaneous endoscopic gastrostomy (PEG) rejected.
|Attention deficit hyperactivity disorder (ADHD), problems in school, depression||Borderline personality disorder||A: initially presented to human genetic specialists by foster parents because of positive HD family history.|
CE: fine motor skills problems in initial testing.
FD: EEG with abnormal findings, without therapeutic consequences.
TA: refrain of therapy with dopamine agonists (e.g., pramipexole) due to optical hallucinations. Psychiatric symptoms more severe and main symptoms, motoric symptoms with slight tremor and rigidity. Low-dose risperidone (reduction of irritability and aggressive behavior), quetiapine, venlafaxine (as an antidepressant with only moderate success) and clozapine (because risperidone was not tolerated in higher doses). Clozapine improved emotional instability and psychosis but also tremor.
CD: earlier multiple suicide attempts (taking tablets, drinking solvents and swallowing razor blades). Patient is now an adult with a stable course and stabilized psychiatric symptoms in the course of the disease. Works in a workshop facility, accommodated in residential facility.
|ADHD, problems in school, behavioral problems||A: initially diagnosed and treated as ADHD by unconnected children psychiatry, massive behavior problems. Before inconspicuous infancy (except for a slight delay in speech development). Methylphenidate (to improve attention problems) without lasting success. Patient then reconsidered as “not trainable”. |
CE: discreet bradykinesia, discreet intention tremor. Fine motoric skill disturbance and increased muscle tone of the lower extremities. Afterward molecular genetic HD diagnosis.
FD: pathological EEG without seizures.
SM: Aggressive behavior towards other children and adults. Massive crimes documented by police with aggression at the age of six years (documented rape attempt on a girl, robbery on an elderly woman and theft of a handbag in the age of 12) led to in- patient diagnostics in a child and youth psychiatry. Persistent behavioral problems with short attention span, lack of controllability for own behavior and verbal aggression persisted. Diagnosis however led to correction of expectations and consequently to relaxing of the loaded situation.
TA: risperidone (improved situation), zuclopenthixole (positive influence on irritability) stabilized conditions.
|Motor abnormalities increasingly occurred on the left side||Epilepsy||A/CE: Expressive speech development delay (received speech therapy). Increasing dystonia of the left foot, three years after the first motoric symptoms and following genetic HD testing. Increasing lethargy in the course of disease, dystrophic (weight < 3 percentile, length < 3 percentile). Saccadic eye movement, chameleon tongue, dystonia of left foot, tremor, bradykinesia, increased muscle tone and reflexes.|
FD: pathological EEG.
TA: venlafaxine or tetrabenazine suggested (lethargy). Various pharmaceutical trials (including L-dopa, amantadine, trihexyphenidyl) without success.
CD: Tonic- clonic movement considered as a seizure and valproate used as an anticonvulsive. Dronabinol at request of mother improved dystonia.
|Bradykinesia, progressive loss of concentration||A: positive family anamnesis, but initially no genetic testing wanted by patient and mother. |
TA: After several frustrating trials with pharmaceutical treatments, Deep brain stimulation (DBS): stereotactic implant of electrons in globus pallidus both sides. An initially setting effect with reduction of dystonia and rigor leading to a better body posture, better fine motor activity and less blepharospasm but worsening of gait and postural instability reported, in summary no significant objective long-term effect. Additional quetiapine, L-dopa/benserazide, pramipexole, seroquel. Fresurbin through PEG. Dopa- induced psychosis (optic and acoustic hallucination) lead to reduction of madopar.
CD/SM: Hypersalivations and frequently bronchopneumonia. Organization of a school accompaniment.
|Progressive movement disorders with hypokinetic- rigid aspects||Motoric axonal polyneuropathy DD: critical illness polyneuropathy||A: initially no genetic testing wanted by patient and mother (brother of case 8). |
TA/CD: Initially Madopar and memantine for cognitive symptoms afterwards DBS without beneficial effect, PEG with dislocation/ hematin vomiting, hypernatremia/ thrombopenia, respiratory decompensation. Urine, defecation-incontinence. Intermittent beneficial botulinum-toxin injection for treatment of dystonia in upper-extremity. Progressing exanthema (better after stopping of sifrol, Nexium, sirdalud). Amantadine, rotigotine lead to an improvement and better position of contract arms/ head. Due to ill skin loss of water with hypertonic dehydration. Topramax due to dystonia lead to an improvement of tremor. Additionally cannabinoids (Sativex-Spray©) leads to marked improvement of dystonia.
SM: organization of a school accompaniment.
|Psychiatric symptoms with attacks of suffocation and heart-pain without clinical correlate, depression||Sudden infantile death syndrome with reanimation||A: At the age of 23 already lived in a care home without HD diagnosis. Before multiple times inpatient in psychiatry because of panic attacks. Post-traumatic stress disorder (PTSD, no further circumstances described). Reported on unspecific described general pain of the whole body during clinical assessments.|
CE: stiff movement disorder, dysarthria.
TA: Trials with baclofen, lorazepam, madopar, mirtazapine, seroquel, tolperisone, amantadine. L-dopa improved movement disorder with “more fluid”. mydocalm (pain) improved sleep, before suffering from nightmares. Stop of amantadine, instead memantine and artane (dystonic posture of the head) lead to a better movement of motoric and psychiatric situation.
|Motoric restlessness and multiple psychiatric problems||A/SM: Since early childhood psycho- social conflict situations and multiple continuous mistreatments due to father who made the patient alcohol- dependent at the age of two. Mistreated with cigarette pushing against the arm and aggressive behavior. Afterwards lived with grandfather (by care).|
TA: ritalin initially, later risperidone, valproate, tiapride
CD: challenging loss of weight, swallowing and chewing difficulties.
|Aggressive behavior and hyper movement of eyes||Epilepsy|
|A: Loss of concentration, difficulties finding words and loss of memory. A described reduction of intelligence. |
FD: MRI with bilateral signal increase Globus pallidus calcification and symmetric expansion of the lateral ventricle.
SM: psycho-social conflict situation in family with massive problems: traumatic situations (saw brother drowning, diverse partners of mother mistreated the patient and mother).
TA: valproate (Convulex) for epilepsy resulted also in less agitation and aggressive behavior after risperidone.
CD: swallowing and chewing difficulties.
|13m→P→Extended CAG, without reporting of exact repeat length→14→17→P|
|Changing of speech and bradykinesia||A/CE: aggressive behavior and bradykinetic rigid movement disorder.|
FD: computed tomography (CT) with atrophy of Caput nuclei caudate and expansion of lateral ventricle front horns.
SM: increased alcohol abuse since the age of 18, marihuana abuse (treated around the age of 15–17), worked in supervised workshop.
TA: Rotigotine- pavement lead to improvement of movement. Bupropion (elontril) lead to an improvement of impulsive behavior, additionally Seroquel.
|14m→P→Extended CAG, without reporting of exact repeat length→6→8→M|
|Conflicts and aggressive behavior||CE: bradykinesia with worsening of movements. |
SM: Lived in a boarding school, before in a care family, aggressive behavior with impulsive outbursts. Nicotine abuse.
TA: ebixia, lamictal, cipramil and requip (as dopaminergic stimulation) lead to an improvement of symptoms.
|Dystonic-hypokinetic symptoms, loss of concentration||Bronchial asthma, atopic dermatitis||A/CE: Worsening of fine motor skills (writing) and loss of concentration. Drug abuse until the age of 23 (marihuana, PEP, cocaine), intermittent alcohol abuse and nicotine abuse. Stopped clinical evaluation and inpatient therapy herself because she already felt an improvement of symptoms.|
TA: Requip modutap lead to a better gang picture and better fine motoric skills. Did not take medication further. Second inpatient evaluation, again discharge against medical advice (she did not see an improvement). Berotec inhaler (if needed for distress), novaminsulfon (due to chronic pain), trial with tetrabenazine stopped due to a described “Heart pain”.
|16m→J→Extended CAG, without reporting of exact repeat length→20→25→P|
|Hyperkinesia motoric clumsiness||Drug-induced parkinsonism||A/CE: Molecular genetic testing due to hyperkinesia. Description of a rapidly massive worsening of chorea during 3-4 weeks.|
TA: Induced increasing of tiapride, swallowing problems, fatigue and no improvement of chorea, more a subjective worsening and parkinsonism. Because of the side effect and expected same side effects of other typical postsynaptic neuroleptics: Therapeutic target with tetrabenazine which improved symptoms very well (tiapride, tetrabenazine and trihexyphenidyl in combination) with three further stable years.
CD/TA: at the age of 28 more dystonia and myocloniform hyperkinesia lead to a trial with valproate and reduced tiapride, tetrabenazine with satisfying improving of symptoms.
|17f→J→Extended CAG, without reporting of exact repeat length→20→23→unknown, no HD family history|
|Agitation, cognitive deficits||Emotionally unstable personality disorder||A/CE: Speech problems, swallowing problems, movement disorder in terms of gear insecurity, problems with coordinative movements.|
SM: Reporting on conflicts concerning the social background, lack of care. Aggressive and oppositional behavior, depression with suicidal ideation. Went to a special school, but without school-leaving certificate and lived in a residential facility because of integration problems.
TA: Initial treatment with sulpiride, discontinuing of medication lead to an improvement. Lamictal induced because of fluctuation of affliction, amantadine lead to visual hallucination, theophylline, Broncho spray, Belladonysat additional.
|Tremor||A/CE: Initially tremor, described by parents and patient. Intermittent suicidal thoughts, aggressive and irritable behavior. |
Posture and action tremor in clinical assessment, also tremor of the tongue. Only very slight intermittent hyperkinesia, more bradykinesia and rigid tone.
TA: citalopram in combination with quetiapine and dopamine-agonist pramipexole initially in small doses due to danger of psychotic disorder lead to an improvement.
|A: massive psychiatric symptoms with depression, irritability, aggressive behavior, perseverative/obsessive behavior. |
FD: EEG with evidence of spike-wave-complexes left parietal.
TA: Difficult pharmacological situation due to recurring unrest and fatigue: Trials with L-thyrox, levetiracetam, mirtazapine, nitoman, lamotrigine, zuclopenthixole (because of affective disorder and irritability). Challenging BOL hyperkinesia (improved after tetrabenazine), reduction of levetiracetam improved fatigue. Pharmaceutical trials with tiapride, sulpiride, gabapentin, pipamperone.
CD/TA: Dysarthria, suicidal attempt, jumped from fifth floor with incomplete paraparesis. More myoclonic movement disorder in upper extremities lead to a treatment with valproate.
Dystonic tetra paresis
|CE: dystonia, hypokinetic movement disorder with spasticity.|
TA: Madopar lead initially to worsening, medication was stopped. Lioseral against spasticity lead to an improvement of symptoms.
CD/TA: Tremor, increasing of creatine kinase and fever lead to the diagnosing of a malignant neuroleptic syndrome (MNS) which was stable after discontinuing the medication. Increase of spasticity and psychotic behavior lead to trials with tavor, cipramil, lioresal, seroquel, zuclopenthixole. Before massive psycho-motoric unrest with attacks of screaming. Intermittent infections (bronchopulmonary due to aspiration?). Trials with levodopa, oxazepam, diazepam, keppra, nexium, baclofen, seroquel, tolperisone, durogenesic patch, tizanidine. As needed: tavor (fear and restlessness), melperon (restlessness), diazepam (spasticity or seizure).
|Psychiatric symptoms, depression. Hyperkinesia||Sterilization||CE: only slight hyperkinesia initially (trunk, extremities).|
FD: MRI with extension of the lateral ventricles and lateral ventricle anterior horns.
CD: Massive loss of weight (20 kg in two years) and recurring infections. Changing of sleep- awake rhythm (trial with mirtazapine improved situation). Tiapride and tetrabenazine stabilized motoric and psychiatric situation.
|Hyperkinesia and motoric clumsiness, depression||Thoracicosteochondrosis||CE: Hyperkinesia and a combination of dystonic components as part of the movement disorder.|
SM: finished school and professional training.
FD: MRI with subcortical atrophy.
CD/TA: Suicidal ideation (driving against a tree), self-harming behavior and sleep disorder. Mirtazapine, tiapride improved situation greatly. Increasing aggressive behavior lead to trials with citalopram, valproate, risperidone, arcoxia, memantine, zopiclone, pipamperone, elontril, tavor. Because of BOL- hyperkinesia botox was induced into the masseter. Disclaiming of food intake, massive perseverative behavior and decubitus during hospitalization. Changing of day/night rhythm = better after reduction of clozapine and increase of Haloperidol. Urine, defecation- incontinence.
|Restlessness, worsening of fine motoric skills||CE/TA: Loss of concentration plus senso-motoric dysarthria. Hypokinetic- rigid symptoms with good response of levodopa, long lasting dopamine-agonist starting with pramipexole ret. |
CD/TA: Worsening of bradykinesia, tendency to fall. Trial with amantadine, quetiapine because of a sleep disorder, zopiclone as needed.
|24f→J→66→19→21→unknown, no HD family history|
|Hyperkinesia and restlessness.||Epilepsy with grand mal seizure||CE: Initially ocular interrupted pursuits, increased saccade latency and slow velocity. Fine motoric movement disorders with finger taps/ pronate supinate hands severe slowing and irregular.|
TA: Tetrabenazine even before diagnosis of HD, baclofen for dystonia. Diazepam for treatment of epilepsy.
CD: suffered from slight intermittent chorea in combination with marked/ prolonged dystonia especially in upper extremities and markedly slow bradykinesia
|Psychiatric symptoms||Allergic asthma||A/CE: Violent/aggressive behavior, apathy, perseverative, obsessive behavior. Chorea only slight/intermittent BOL/Trunk. Fine motoric skills difficulties, saccades and ocular pursuit. Previous suicidal attempts. |
TA: escitalopram (obsessive-compulsion) and quetiapine (mood stabilization) improved situation.
|Demographics||Pediatric (N = 18)||Juvenile (N = 14)|
|Male/female sex (%)||72.2/27.8||42.9/57.1|
|CAG- repeat-expansion length||67.3 (SD 11.6, n = 14)||57.4, SD 5.6, n = 11)|
|Age of onset (AO) (years)||10.3 (SD 4.1, n = 16)||19.3 (SD 0.9, n = 14)|
|Age of diagnosis (AD) (years)||13.5 (SD 3.8, n = 17)||23.2 (SD 1.2, n = 9)|
|Mean time between AO and AD (years)||3.5 (SD 1.9, n = 15)||3.0 (SD 1.0, n = 9)|
|Paternal/maternal inheritance||68.8/ 31.2 (n = 16)||71.4/28.6 (n = 7)|
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