J Inherit Metab Dis DOI 10.1007/s10545-014-9789-1
ORIGINAL ARTICLE
Cognitive profile of patients with glycogen storage disease type III: a clinical description of seven cases Claire-Cécile Michon & Marcela Gargiulo & Valérie Hahn-Barma & François Petit & Aleksandra Nadaj-Pakleza & Ariane Herson & Bruno Eymard & Philippe Labrune & Pascal Laforet
Received: 24 March 2014 / Revised: 4 August 2014 / Accepted: 29 October 2014 # SSIEM 2014
Abstract Background Glycogen storage disease type III (GSDIII) is a rare autosomal recessive disorder due to glycogen debranching enzyme (GDE) deficiency. It results in a multisystemic disease with predominant hepatic and myopathic symptoms. While frequent social maladjustment has been observed in our clinical practice, cognitive and psychological disturbances have never been assessed. The aim of this
Communicated by: Peter Burgard C. T), one nonsense mutation (c.1783C > T), two splicing mutations (c.82+1G > A, 664+1G > A), two insertions (c.3178_3179insT, c.4323_4324insAA), and one deletion (c.4456delT). Among these, four were novel: c.82+ 1G > A, c.3178_3179insA, 664+1G > A, and c.1078C > T. Patients A to E were compound heterozygotes whereas patients F and G were homozygotes for the same mutation. Psychopathological findings (Table 3) According to the MINI, five of the seven patients had a history of depression and three had a history of generalized anxiety disorders. According to the SAS-SR, three were socially maladjusted. An anxiety state was revealed in five patients using the STAI Y-A and an anxiety trait was found in six patients using the STAI Y-B. Neuropsychological findings (Table 4)
Global efficiency Three patients had impaired global efficiency on assessment using the MMSE and four on the MATTIS test. Domains most impaired were conceptualization and initiation, which are particularly sensitive to executive functions. At the MMSE 6/7 patients presented difficulties for the attentional item (to count from one hundred and remove seven each time), and five patients out of these six also lost a point to the phrase repetition, which can also be considered as attentional. Two patients (patients E and F) lost points at the orientations questions and at the drawing, and only one (patient D) lost his point to the recall of one word on the three (gave a phonemic similar word).
Clinical and neuroradiological features Working memory All patients presented liver enlargement and experienced hypoglycaemic episodes during childhood, followed by the occurrence of exercise intolerance and fixed muscle weakness
Working memory was impaired for five patients on the forward and backward digit span, considering that working
Carbohydrate rich None None 5xN 9xN 6xN Walk without aid + Intermittent wheelchair – Walk without aid –
Carbohydrate rich 10xN
1.5xN High protein
Walk without aid + Intermittent wheelchair + Walk without aid +
None 10xN – Walk without aid
memory is impaired when the difference between the forward digit span and the backward one is greater than or equal to 2. Memory Memory measured by the FRCT was preserved. Recall skills in memory are linked to executive functions related to frontal activities, memory skills (coding) are linked to parietal activities, and storage and consolidation skills are linked to temporal activities. Language One patient (F) presented anomia in denomination of 12 pictures. Regarding verbal fluencies (included fluencies in the FAB), four patients obtained below average scores in phonemic fluency which requires more flexibility process of strategies.
– + – + + +
4.8 3.8 3.5
+ – – + + +
3.9 3.7 4.3
+ +
4.3
Visual construction skills Difficulties for simple figures from the MMSE were present in two patients. In coping with the Rey figure, three patients began with a detail before continuing with the main rectangle (type II), one drew the shape of the figure to place the other elements inside (type III), and one used a juxtaposition of the various elements of the figure (type IV) reflecting difficulties in visuo-spatial planning.
66/25 96/37 60/24 R R R 8 9 12 F F F 44 49 51 E F G
*obtained by a single question (R Right-handed; L Left-handed; A Ambidextrous)
73/30 95/33 60/26 R L A 11 11 11 F M F 33 36 38 B C D
Two patients obtained scores under the cut-off point on the FAB, two others on the frontal score, and one on both scales. In the M-WSCT we observed many perseverative errors and a failure to maintain a set of criteria. Three patients had difficulties in a switching task (TMT B), one had an increased sensitivity to interference (Stroop) and two exhibited a pathological slowing down in the three conditions. Planning difficulties were observed during the Rey figure copy for all the patients. In summary, five patients presented a dysexecutive syndrome. **repeated 3 years during schooling
79/24 20
F
15
3 years of university High school Youth training Youth training** College College High school
R
Executive functions
A
Seizures/severe Fasting blood Functional Handedness* Weight (kg) Liver BMI (kg/m2) enlargement hypoglycaemia glucose (mM) capacities in childhood Patient Age Gender Years of Level of education education
Table 1 Presentation of the seven patients with GSD III
Cardio CK myopathy
Current dietary regimen
J Inherit Metab Dis
Emotional skills Four patients had difficulties in identifying the six primary emotions of Ekman, in particular fear and anger, and four obtained very low theory of mind scores, while control score for comprehension was normal in three of them. Three patients obtained a score suggestive of apathy. Important attention fluctuations were observed in all patients during the examination, with difficulties to maintain their attention. After the complete assessment, 4/7 patients
J Inherit Metab Dis Table 2 Molecular analysis Allele 1
Allele 2
DNA level
Predicted protein
Reference
DNA level
Predicted protein
Reference
A B
c.82+1G > A* c.1783C > T
Splicing p.Arg595X
Novel Aoyama et al, 2009
c.3178_3179insT* c.4323_4324insAA
p.ser1060PhefsX10 p.Gly1442ArgfsX9
novel Lucchiari et al, 2,002
C D
c.664+1G > A* c.1078C > T*
Splicing p.His360Tyr
Novel Novel
c.664+1G > A* c.4456delT
splicing p.Ser1486ProfsX18
novel Parvari et al, 1997
E
c.4323_4324insAA
p.Gly1442ArgfsX9
Lucchiari et al, 2002
c.4323_4324insAA
p.Gly1442ArgfsX9
Lucchiari et al, 2002
F G
c.1078C > T* c.1078C > T*
p.His360Tyr p.His360Tyr
Novel Novel
c.1078C > T* c.1078C > T*
p.His360Tyr p.His360Tyr
novel novel
*new mutation
reported spontaneously to have attentional difficulties in their everyday life.
Discussion The aim of this study was to detect psychological and cognitive impairments in subjects affected by GSDIII. The results of neuropsychological analysis showed that only one patient with the shortest duration of the disease (A) had no neuropsychological troubles. Another patient (D) had neither dysexecutive syndrome nor socio-emotional difficulties, but presented important attention fluctuations. All five other patients had dysexecutive syndrome which included some combination of symptoms such as an impairment of working memory, planning skills, the capacity to elaborate and maintain strategies, conceptualization and rule generation, and a generalized slowness. In these five patients we also observed an impairment of emotional recognition and/or theory of mind that might arise from medial prefrontal and orbitofrontal cortices dysfunction, possibly explaining socioemotional difficulties. However, instrumental functions and memory skills were largely preserved. Therefore, we observed
Table 3 Scores obtained on the psychopathological scales
significant psychopathological and neuropsychological impairment in adult patients with GSDIII. It is noteworthy that 5/7 patients obtained a global score under the cut-off at the Mattis scale and two patients out of these five also obtained a deficit score at the MMS. The choice of the DRS can be criticized because of the lack of standards for a population aged under 60. However it did constitute an interesting tool for a first screening and enables to bring out a central dysfunction. All patients also had a history of mild psychiatric troubles with generalized anxiety disorder, depression or social maladjustment. Due to the small size of our cohort, we cannot exclude that anxiety and depression that we observed could be rather a co-morbidity than associated to the disease, because of the prevalence of these problems in the general population and in chronic neurological diseases. However, because of the high frequency of such psychopathological disturbances observed in our cohort, contrasting with a moderate disease severity, it is unlikely that the severity of the disease itself could explain the psychopathological troubles. By contrast, Gargiulo et al (Gargiulo et al 2013) demonstrated that there is no psychopathological disturbances in patients with GSDII which are more severely physically handicapped. This observation enables us to hypothesize the existence of a
Patients
SAS-SRa
STAI Y-Ab
STAI Y-Bb
Psychopathological assessment by MINI
A B
2 1.3
60 41
63 40
C D E F G
1.5 1.8 2.5 4.3 4
45 38 57 56 71
47 48 61 48 78
Generalised anxiety current and past Major depressive episodes past, panic attacks past, post traumatic stress past Major depressive episodes past Major depressive episodes past, hypomania Major depressive episodee current and past Impractical Major depressive episodes current and past
a
SAS-SR scores: from 1 to 2: normal, 3: mild difficulties, 4: moderate.
b State anxiety scores: 65: very high
J Inherit Metab Dis Table 4 Neuropsychological analysis (results in bold are considered pathological) A
B
C
D
E
F
G
Mean SD
Scores
ORIGINAL ARTICLE
Cognitive profile of patients with glycogen storage disease type III: a clinical description of seven cases Claire-Cécile Michon & Marcela Gargiulo & Valérie Hahn-Barma & François Petit & Aleksandra Nadaj-Pakleza & Ariane Herson & Bruno Eymard & Philippe Labrune & Pascal Laforet
Received: 24 March 2014 / Revised: 4 August 2014 / Accepted: 29 October 2014 # SSIEM 2014
Abstract Background Glycogen storage disease type III (GSDIII) is a rare autosomal recessive disorder due to glycogen debranching enzyme (GDE) deficiency. It results in a multisystemic disease with predominant hepatic and myopathic symptoms. While frequent social maladjustment has been observed in our clinical practice, cognitive and psychological disturbances have never been assessed. The aim of this
Communicated by: Peter Burgard C. T), one nonsense mutation (c.1783C > T), two splicing mutations (c.82+1G > A, 664+1G > A), two insertions (c.3178_3179insT, c.4323_4324insAA), and one deletion (c.4456delT). Among these, four were novel: c.82+ 1G > A, c.3178_3179insA, 664+1G > A, and c.1078C > T. Patients A to E were compound heterozygotes whereas patients F and G were homozygotes for the same mutation. Psychopathological findings (Table 3) According to the MINI, five of the seven patients had a history of depression and three had a history of generalized anxiety disorders. According to the SAS-SR, three were socially maladjusted. An anxiety state was revealed in five patients using the STAI Y-A and an anxiety trait was found in six patients using the STAI Y-B. Neuropsychological findings (Table 4)
Global efficiency Three patients had impaired global efficiency on assessment using the MMSE and four on the MATTIS test. Domains most impaired were conceptualization and initiation, which are particularly sensitive to executive functions. At the MMSE 6/7 patients presented difficulties for the attentional item (to count from one hundred and remove seven each time), and five patients out of these six also lost a point to the phrase repetition, which can also be considered as attentional. Two patients (patients E and F) lost points at the orientations questions and at the drawing, and only one (patient D) lost his point to the recall of one word on the three (gave a phonemic similar word).
Clinical and neuroradiological features Working memory All patients presented liver enlargement and experienced hypoglycaemic episodes during childhood, followed by the occurrence of exercise intolerance and fixed muscle weakness
Working memory was impaired for five patients on the forward and backward digit span, considering that working
Carbohydrate rich None None 5xN 9xN 6xN Walk without aid + Intermittent wheelchair – Walk without aid –
Carbohydrate rich 10xN
1.5xN High protein
Walk without aid + Intermittent wheelchair + Walk without aid +
None 10xN – Walk without aid
memory is impaired when the difference between the forward digit span and the backward one is greater than or equal to 2. Memory Memory measured by the FRCT was preserved. Recall skills in memory are linked to executive functions related to frontal activities, memory skills (coding) are linked to parietal activities, and storage and consolidation skills are linked to temporal activities. Language One patient (F) presented anomia in denomination of 12 pictures. Regarding verbal fluencies (included fluencies in the FAB), four patients obtained below average scores in phonemic fluency which requires more flexibility process of strategies.
– + – + + +
4.8 3.8 3.5
+ – – + + +
3.9 3.7 4.3
+ +
4.3
Visual construction skills Difficulties for simple figures from the MMSE were present in two patients. In coping with the Rey figure, three patients began with a detail before continuing with the main rectangle (type II), one drew the shape of the figure to place the other elements inside (type III), and one used a juxtaposition of the various elements of the figure (type IV) reflecting difficulties in visuo-spatial planning.
66/25 96/37 60/24 R R R 8 9 12 F F F 44 49 51 E F G
*obtained by a single question (R Right-handed; L Left-handed; A Ambidextrous)
73/30 95/33 60/26 R L A 11 11 11 F M F 33 36 38 B C D
Two patients obtained scores under the cut-off point on the FAB, two others on the frontal score, and one on both scales. In the M-WSCT we observed many perseverative errors and a failure to maintain a set of criteria. Three patients had difficulties in a switching task (TMT B), one had an increased sensitivity to interference (Stroop) and two exhibited a pathological slowing down in the three conditions. Planning difficulties were observed during the Rey figure copy for all the patients. In summary, five patients presented a dysexecutive syndrome. **repeated 3 years during schooling
79/24 20
F
15
3 years of university High school Youth training Youth training** College College High school
R
Executive functions
A
Seizures/severe Fasting blood Functional Handedness* Weight (kg) Liver BMI (kg/m2) enlargement hypoglycaemia glucose (mM) capacities in childhood Patient Age Gender Years of Level of education education
Table 1 Presentation of the seven patients with GSD III
Cardio CK myopathy
Current dietary regimen
J Inherit Metab Dis
Emotional skills Four patients had difficulties in identifying the six primary emotions of Ekman, in particular fear and anger, and four obtained very low theory of mind scores, while control score for comprehension was normal in three of them. Three patients obtained a score suggestive of apathy. Important attention fluctuations were observed in all patients during the examination, with difficulties to maintain their attention. After the complete assessment, 4/7 patients
J Inherit Metab Dis Table 2 Molecular analysis Allele 1
Allele 2
DNA level
Predicted protein
Reference
DNA level
Predicted protein
Reference
A B
c.82+1G > A* c.1783C > T
Splicing p.Arg595X
Novel Aoyama et al, 2009
c.3178_3179insT* c.4323_4324insAA
p.ser1060PhefsX10 p.Gly1442ArgfsX9
novel Lucchiari et al, 2,002
C D
c.664+1G > A* c.1078C > T*
Splicing p.His360Tyr
Novel Novel
c.664+1G > A* c.4456delT
splicing p.Ser1486ProfsX18
novel Parvari et al, 1997
E
c.4323_4324insAA
p.Gly1442ArgfsX9
Lucchiari et al, 2002
c.4323_4324insAA
p.Gly1442ArgfsX9
Lucchiari et al, 2002
F G
c.1078C > T* c.1078C > T*
p.His360Tyr p.His360Tyr
Novel Novel
c.1078C > T* c.1078C > T*
p.His360Tyr p.His360Tyr
novel novel
*new mutation
reported spontaneously to have attentional difficulties in their everyday life.
Discussion The aim of this study was to detect psychological and cognitive impairments in subjects affected by GSDIII. The results of neuropsychological analysis showed that only one patient with the shortest duration of the disease (A) had no neuropsychological troubles. Another patient (D) had neither dysexecutive syndrome nor socio-emotional difficulties, but presented important attention fluctuations. All five other patients had dysexecutive syndrome which included some combination of symptoms such as an impairment of working memory, planning skills, the capacity to elaborate and maintain strategies, conceptualization and rule generation, and a generalized slowness. In these five patients we also observed an impairment of emotional recognition and/or theory of mind that might arise from medial prefrontal and orbitofrontal cortices dysfunction, possibly explaining socioemotional difficulties. However, instrumental functions and memory skills were largely preserved. Therefore, we observed
Table 3 Scores obtained on the psychopathological scales
significant psychopathological and neuropsychological impairment in adult patients with GSDIII. It is noteworthy that 5/7 patients obtained a global score under the cut-off at the Mattis scale and two patients out of these five also obtained a deficit score at the MMS. The choice of the DRS can be criticized because of the lack of standards for a population aged under 60. However it did constitute an interesting tool for a first screening and enables to bring out a central dysfunction. All patients also had a history of mild psychiatric troubles with generalized anxiety disorder, depression or social maladjustment. Due to the small size of our cohort, we cannot exclude that anxiety and depression that we observed could be rather a co-morbidity than associated to the disease, because of the prevalence of these problems in the general population and in chronic neurological diseases. However, because of the high frequency of such psychopathological disturbances observed in our cohort, contrasting with a moderate disease severity, it is unlikely that the severity of the disease itself could explain the psychopathological troubles. By contrast, Gargiulo et al (Gargiulo et al 2013) demonstrated that there is no psychopathological disturbances in patients with GSDII which are more severely physically handicapped. This observation enables us to hypothesize the existence of a
Patients
SAS-SRa
STAI Y-Ab
STAI Y-Bb
Psychopathological assessment by MINI
A B
2 1.3
60 41
63 40
C D E F G
1.5 1.8 2.5 4.3 4
45 38 57 56 71
47 48 61 48 78
Generalised anxiety current and past Major depressive episodes past, panic attacks past, post traumatic stress past Major depressive episodes past Major depressive episodes past, hypomania Major depressive episodee current and past Impractical Major depressive episodes current and past
a
SAS-SR scores: from 1 to 2: normal, 3: mild difficulties, 4: moderate.
b State anxiety scores: 65: very high
J Inherit Metab Dis Table 4 Neuropsychological analysis (results in bold are considered pathological) A
B
C
D
E
F
G
Mean SD
Scores
