Paucar1
Progressive brain calcifications and signs in a family with the L9R mutation in the PDGFB gene
- Clinical synopsis:
Very little is known about the natural history of PDGFB-associated PFBC. So far, nine PDGFB mutations have been described (1–6). Four patients from the F13 family (a father and three siblings) harboring the c.26T>G (L9R) mutation in exon 1 of the PDGFB gene (1) were evaluated clinically and went through radiological and biochemical studies. The pedigree is displayed in figure e-1. Mean time for clinical follow up was 5.5 years and between first and last brain CT scans was 4.8 years. The study was approved by the local ethics committee and the radiation protection organization at the Karolinska University Hospital (Etikprövningsnämndendnr 2013/924-31).
At the time of PFBC diagnosis all the affected patients (four in total) met the criteria for migraine with aura, mean age at onset of migraine was 13.8 (range 12-16) (1). Mean age at last exam was 35.5 years (range 23-59). The following motor scales were used in our assessment: Tremor rating scale (TRS), Unified Parkinson’s disease rating scale (UPDRS) part III, Unified Huntington’s disease rating scale (UHDRS), Scale for the Assessment and Rating of Ataxia (SARA) and Inventory of non-ataxia Symptoms (INAS). Mean age at onset for a movement disorders was 28.25 (range 17-52). All the participants reported varying degrees of action tremor as the first movement disorder. The motor scores and radiological findings are summarized in table e-1. Ages at onset are summarized in table e-2. The degree of calcification on base line exams was determined using the total calcification score (TCS) (3). The rate of calcification progression was evaluated using both the TCS and the co-registration method described in this paper. We also attempted to measure the density of hydroxyapatite (HA) in calcified brain areas. Details of the radiological methods and results are summarized in tables e-5 to e-9. Biochemical analyses are summarized in table e-10.
The patients were also screened with the Hospital Anxiety and Depression Scale (HAD-A and HAD-D). More than 10 points in each subscale indicates possible depression or anxiety. Neuropsychological testing of the index case III:1 (2009 and 2015) and III:3 (2015/2016) were performed using the following batteries: 1. Brief cognitive status: Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE); 2. General intellectual ability (IQ): Ravens progressive matrices; 3. Evaluation of verbal episodic memory: Rey Auditory Verbal Learning Test RAVLT (RAVLT); 4. Visuospatial episodic memory: Rey Osterrieth Complex Figure Test (ROCFT); 5. Working memory: digit span of the Wechsler Adult Intelligence Scale (WAIS-III); 6. Spatial/visual construction: ROCFT, Copy and Block Design/WAIS; 7. Verbal concept formation: Similarities in WAIS-III; 8. Word fluency: Controlled Oral Word Association Test (FAS/COWAT); 9. Picture Naming: Boston Naming Test (BNT); 10. Information processing speed: Symbol Digit Modalities Test (SDMT); 11. Executive function: Trail Making Test, B (TMT); 12. Motor speed: Finger-tapping test (FT), dominant and non-dominant hand. Zscores which were computed on the basis of reference values from test manuals and handbooks were used to compare results from various tests (7,8). A z score ≤ -1.5 SD is compatible with a significant cognitive deficit. Patients II:3 and III:2 did not undergoa planned cognitive evaluation. The cognitive and language features are summarized in tables e-3 and e-4.In this study we demonstrate progressive brain calcifications and symptoms. To illustrate the motor progression we provide video recordings from two different occasions, for subject II:3 we have 3 video recordings (supplementary material). Due to progression the patients were offered treatment with clodronic acid based on the effect of bisphosphonates described in a previous report (9). The long term effect of this treatment will be reported later.
1.1Case II:3
This is a 59 year old male, born in Finland, with roots in the Karelia region.He attended school for 9 years, came to Sweden in 1976 and has worked as a truck driver for many years. During the last two years he started to worknight shifts. He is a smoker; his past medical history (PMH) consists of migraine with aura with onset at the age of 13. He underwent 3 surgical procedures in the left shoulder due to rupture of the supraspinatus tendon and impingement in the left shoulder. Theprocedures were performed in 2009 and 2011, neverthelesshe has recurrent pain in this region.He also has a history of anxiety and recurrent depressions requiring periodical pharmacological treatment. During some of these past episodes he likely met the criteria for alcohol use disorder but denies current abuse. He described insidiousaction tremor starting at the age of 52 for which he was intermittingly used propranolol. He also complained of impaired short term memory, a recent screening with Montreal Cognitive Assessment (MoCA) yielded 25 points. Briefly, deficits were found in delayed recall, attention, visuospatial abilities and word fluency. His HAD-A was 14 and HAD-D was 9. The patient did not comply with a planned cognitive evaluation andwas reluctant to start antidepressant treatment.A widespread chronic skin infectionaffecting his back prevented a lumbar puncture. The subject has described numbness in both arms, the age at onset of this symptom isunclear, he did not comply with a planned electroneurography (ENeG) and electromyography (EMG). Recently, vitamin B12 deficiency was diagnosed and replenishment recommended but again he declined to follow this recommendation. Gynecomastia was found on exam.
His motor features are subtle(video 1). Since the first physical exam in 2010 we found reduced dexterity on the left side when the patient performed alternating hand movements. In the first exam fine rapid postural tremor, mild dystonic posturing of the right hand, mild chorea in the legs and bilateral mild dysmetria on finger chase were also evident. His ability to walk tandem and his left leg agility have become mildly impaired over time. We also found jerky smooth pursuit, single nystagmus beats on secondary position and suggestion of hypermetric centripetal saccades. The remaining of the neurological exam was unremarkable. His latest motor scores were as follows: TRS 11, UPDRS part III 8, UHDRS 5 and SARA 4.5.
Imaging: Widespread calcifications were found in the lentiformnucleus. Mild calcifications in the white matter of frontal regions were also identified. His TCS of 15 remained unchanged. This is the only subject in this kindred without calcifications in the thalamus, cerebellar or caudate nuclei.
Comment on II:3:A mild motor progression has occurred. Without a deeper cognitive assessment we have to interpret thesuspicionof possible cognitive impairment with caution. The negative impact of shift work on cognitive performance has been characterized before (10). Other factors influencing his outcome are smoking, recurrent depressions and cobalamin deficiency.
1.2Case III:1
This 32 year old femaleis the index case of this family. Onset of migraine with aura was at age 16. She was referred to our center at age 27 due to progressive language difficulties starting two years before. At the time the patient worked in a printing company making signs. Angry costumers complained about signs with typographical errors made by the patient. At the age of 26 she started to notice tremor and impaired dexterity. These symptoms are notoriously exacerbated by stress and by migraine.Most migraine episodes were preceded by recurrent numbness in the right hand and aura. After ruling out common causes of secondary brain calcifications (1)she underwent a muscle biopsy and a lumbar puncture. Both exams yielded normal findings. She suffered from recurrent loss of consciousness, an investigation with long-term ECG monitoring and echocardiography were unremarkable. An EEG under standard conditions and during sleep deprivation was also normal. Syncope occurred during a tilt test in which her systolic blood pressure fell to 40 mmHg and her pulse to 80 beats/minute. These findings were interpreted as compatible with a vasovagal reaction.
Her motor features were also subtle (video 2). Briefly, posturing was evident at age 30, two years later chorea was evident in her feet, finger and head. Dystonic extension of the big toes and posturing of the left third digit were also evident. The patient is not aware of these hyperkinesias. A bilateral mild clumsiness is evident when the subject performs foot stamping. Mild hypometric vertical saccades are also observed. Her latest motor scores were as follows: TRS 9, UPDRS part III 3, UHDRS 8 and SARA 0.
A speech evaluation found preserved grammar and fluency. Her language comprehension and inference capacity were also normal when assessed with the subtle language disorders test (a test for Swedish speakers) (11); with this test significant and persistent difficulties in repetition tasks and reading were found. In addition, clear deficits compatible with anomia were identified with the BNT. During a follow up evaluation at age 32her BNT score improved but remained significantly low. During this follow up verbal and phonemic paraphasias were identifiedas a new feature of her language impairment (table e-4).The patient’s strategy to avoid typographical errors at work is to frequently check what she writes and to have supervision.
She has a total education of 13 years. At the neuropsychological testing 2009 as well as at follow-up 2015, this patient performed clearly above average in comparison with her age group, when tested with Ravens progressive matrices measuring general intellectual ability (IQ 125). A brief cognitive screening with MMT yielded 29/30 points at baseline and 28/30 at follow-up six years later. HerMoCA score was 29/30 in 2015, her HAD-A was 0 and HAD-D was 3. At baseline in 2009, clear deficits were found in tests measuring working memory (Digit span) and Picture Naming (BNT). Tests measuring the following functions were within in the normal range: verbal episodic memory, (RAVLTlearning), visuospatial episodic memory (ROCFT), verbal concept formation (Similarities), word fluency (FAS/COWAT), information processing speed (SDMT), executive function (TMT B) and motor speed on dominant and non-dominant hand (FT). Furthermore in 2009 a result clearly above average was seen in verbal episodic memory, (RAVLTretention) and in tests measuring spatial/visual construction a result ranging from average (ROCFT, copy) to above average (Block design) could be noted. When re-tested in 2015, a score clearly below average remained in digit span. An improvement from within normal range to clearly above average could be seen at follow-up in verbal episodic memory, (RAVLTlearning), word fluency (FAS/COWAT) and motor speed (FT) on non- dominant hand. In the following tests the performance was still in the normal range at follow-up: visuo-spatial episodic memory (ROCFT), verbal concept formation (Similarities), information processing speed (SDMT), executive function (TMT B) and motor speed (FT) on dominant hand. A result clearly above average remained in verbal episodic memory (RAVLTretention) at follow-up (table e-3).
Imaging: CT scans of the brain displays progressive symmetric calcifications in the lentiform and caudate nuclei, dentate nuclei, thalamus and frontal white matter. We also found faint cortical calcifications in the right parietal lobes of III:1, an MRI revealed a small developmental venous anomaly (DVA) in the left frontal region. This finding was considered to lack clinical relevance. Her initial TCS was 34 which increased to 39 after 5 years of follow up.
Comment: This is one of the two cases in this kindred where the TCS detected progression of brain calcifications.The subject displays a complex phenotype with features of mild language impairment (anomia, emergence of paraphasias and persistent impairment in repetition ability), reduced working memory and progressive movement disorders (chorea, tremor and posturing).Her BNT score improved over time indicating variability in the cognitive testing.
1.3CaseIII:2
This 28 year old malehas a PMH of combined alcohol and cannabis abuse. Onset of migraine with aura was at age 14. In 2006 he was involved in a car accident that caused transient neck pain but a CT-scan of this region was normal. Similar to his father, he went through surgery for impingement in the left supraspinatus muscle in 2013. He interrupted his schoolattendance at the age of 12 and has not completed high school education. He has a total education of 9 years. A neuropsychiatric condition has been suspected but not proven yet.
He complained of action induced tremor starting at the age of 18. An exam at age 23 revealed mild right arm chorea at rest, fine and fast postural tremor with occasional negative myoclonus, as well as reduced dexterity when performing alternating hand movements with the left. During the last evaluation in 2015 the patient described persistent action tremor, the appearance of leg cramps, involuntary movements and gait difficulties. The description was suggestive for dystoniawhich was evident on the right foot on walking. Two years later new features were evident: impaired bilateral foot stamping, mild chorea in both feet and tremor on finger-to-nose testing which is more prominent at the endpoint. An increase in muscle tonus in the right arm is noticed only after contralateral activation.Mild abnormal eye movements were also evident:gaze-evoked nystagmus beats, centrifugal hypometric saccades and centripetal hypermetric saccades (video 3). His latest motor scores were as follows: TRS 12, UPDRS part III 6, UHDRS 7 and SARA 1.5.
His MoCAscore was 26 points. In this test attention deficits were evident and to a lesser degree impaired delayed recall and visuospatial skills. At this point his HAD-D was 5 and HAD-A was 11.Despite our attempts the patient did not participate in planned cognitive or psychiatric evaluations.For periods of time the patient withdrew socially. This is the only subject in this family with a mild elevation of albumin in the CSF (Q alb). Nevertheless, oxysterol in plasma and CSF as well as markers of neurodegeneration in the CSF were normal.
Imaging: Symmetric and widespread calcifications are located in the lentiform and caudate nuclei mainly. A moderate degree of calcifications is seen in the thalamus and to a lesser degreein the white matter of the frontal area and in the dentate nuclei. The TCS score of 34 remained unchanged.
Comment: This case is characterized by predominant behavioral features and mild progressive motor features in the context of widespread and marked calcifications in the basal ganglia and to a lesser degree in the thalami, frontal regions and cerebellum.This motor progression, clear chorea,seems to occur in the absence of detectable radiological progression. Whether there is an underlying neuropsychiatric condition and cognitive deficits was not possible to evaluate.
1.4Case III:3
This 23 year old female describes spontaneous migraine remission during the last year. Age at onset of migraine with aura was 12. She developed insidious tremor starting at the age of 17. Her main symptom over time is impaired short memory that also raised complaints at her work. There are no records of learning disabilities during school. She has enrolled recently in a training program in a vocational school. During her pregnancy two years ago she noticed reduced dexterity in her right arm and hand. An EMG revealed chronic neurogenic abnormalities corresponding to the right C5-Th1 myotomes but the ENeG was normal. A MRI of the spinal cord was normal. Physical exams were performed in 2010 and in July 2015.
Physical exam at age 18 revealed fine rapid postural tremor with superimposed jerks, posturing of the wrists and hyperextension of the fingers. Five years later chorea in the lower limbs has emerged, the subject is not aware of those movements. Also evident here are dexterity in her right arm and hypermetric horizontal saccades (video 4). Her latest motor scores were as follows: TRS 10, UPDRS part III 6, UHDRS 8 and SARA 2.
Biochemical analyses revealed a mild elevation of neurofilament light chain (NfL) in her CSF but the other parameters were normal.
She has a total education of 13.5 years. She went through the neuropsychological examination in 2015, at this pointher HAD-D score was 1 and HAD-A 9. When tested with Ravens progressive matrices, this patient reached an average level of general intellectual ability in relation to her age group (IQ 96). A short cognitive screening yielded a MMT and MOCA score of 27/30. A performance clearly below average was seen in tests measuring the following functions: visuospatial episodic memory (ROCFT immediate and delayed recall), working memory (Digit span), spatial/visual-construction (ROCFT copy and Block Design), picture naming (BNT), information processing speed (SDMT) and executive function (TMT B). She also had a mild impairment when repeating foreign polysyllabic words. A performance in the normal range was seen in tests measuring verbal episodic memory (RAVLT), verbal concept formation (Similarities), word fluency (FAS/COWAT) and motor speed (FT) on dominant and non-dominant hand(table e-3).
Imaging: Symmetric and widespread calcifications are found mainly in the thalamus, lentiform and caudate nucleus. Mild calcifications were found in the dentate nucleus, periventricular regions and in the frontal white matter. We also found faint cortical calcifications located in the parietal lobes more predominant on the left side. Herinitial TCS was 37 and in the last assessment 39.