Expanded Newborn Screening for Inborn Errors of Metabolism in Hong Kong: Results and Outcome of a 7 Year Journey.

Newborn screening (NBS) is an important public health program that aims to identify pre-symptomatic healthy babies that will develop significant disease if left undiagnosed and untreated. The number of conditions being screened globally is expanding rapidly in parallel with advances in technology, diagnosis, and treatment availability for these conditions. In Hong Kong, NBS for inborn errors of metabolism (NBSIEM) began as a pilot program in October 2015 and was implemented to all birthing hospitals within the public healthcare system in phases, with completion in October 2020. The number of conditions screened for increased from 21 to 24 in April 2016 and then to 26 in October 2019. The overall recruitment rate of the NBS program was 99.5%. In the period between October 2015 and December 2022, 125,688 newborns were screened and 295 were referred back for abnormal results. The recall rate was reduced from 0.26% to 0.12% after the implementation of second-tier testing. An inherited metabolic disorder (IMD) was eventually confirmed in 47 infants, making the prevalence of IMD in Hong Kong 1 in 2674. At the time of the NBS result, 78.7% of the newborns with IMD were asymptomatic. There were two deaths reported: one newborn with methylmalonic acidemia cobalamin B type (MMACblB) died after the initial crisis and another case of carnitine palmitoyltransferase II deficiency (CPTII) died at 18 months of age after metabolic decompensation. The most common IMD noted were disorders of fatty acid oxidation metabolism (40%, 19 cases), closely followed by disorders of amino acid metabolism (38%, 18 cases), with carnitine uptake defect (19.1%, 9 cases) and citrullinemia type II (17%, 8 cases) being the two most common IMD picked up by the NBSIEM in Hong Kong. Out of the all the IMDs identified, 19.1% belonged to diverse ethnic groups. False negative cases were reported for citrullinemia type II and congenital adrenal hyperplasia during this period.

CYP2U1: An emerging treatable neurometabolic disease with cerebral folate deficiency in 2 Chinese brothers.

With the rapid advancement of medical technologies in genomic and molecular medicine, the number of treatable neurometabolic diseases is quickly expanding. Spastic paraplegia 56 (SPG56), one of the severe autosomal recessive forms of neurodegenerative disorders caused by pathogenic variants in the CYP2U1 gene, has no reported specific targeted treatment yet. Here we report 2 Chinese brothers with CYP2U1 bi-allelic pathogenic variants with cerebral folate deficiency who were treated for over a decade with folinic acid supplement. Patients have remained stable under therapy.

Quality of life and symptom burden in children with neurodegenerative diseases: using PedsQL and SProND, a new symptom-based scale.

BACKGROUND: Children with neurodegenerative conditions (CNDC) often suffer from severe neurodisability and high symptom burden with multisystemic involvement. However, their symptom burden and health-related quality of life (HRQOL) is not systematically documented in the literature, and there is no existing tool for such purposes. We designed our own tool for scoring of symptom burden amongst CNDCs and adopted the PedsQL generic score 4.0 to quantify the impact of overall symptom burden on children's overall HRQOL. METHODS: The Symptom Profile for children with neurodegnerative condition (SProND) questionnaire was developed, which consisted of 14 questions grouped according to 5 categories, namely epilepsy, neurobehavioural, movement and mobility related, breathing and swallowing, and other daily activities. CNDCs were recruited during visits to the Comprehensive Neurometabolic / Neurodegenerative Program of the Duchess of Kent Children's Hospital and Hong Kong Children's Hospital between November 2019 and March 2020. The SProND and PedsQL 4.0 Generic Core Scales were distributed to consenting parents of CNDCs. RESULTS: 36 CNDCs were recruited and matched with community controls. The response rate of subject and control were 99.5% and 98.7% respectively. The Cronbach alpha was 0.61 for the neurobehavioural domain and > = 0.7 for other domains. The greater number of symptoms each subject experiences, the worse his/ her PedsQL scores. Subjects displaying hypersalivation and swallowing difficulties had average physical health summary scores of less than 30% compared with subjects without these symptoms. On the other hand, average psychosocial health summary scores of subjects with involuntary movements, joint stiffness, hypersalivation, sleep problem and anorexia were approximately 70% compared to subjects without these symptoms. DISCUSSION AND CONCLUSION: This is one of the first studies to look at CNDCs as a group. We propose the SProND questionnaire for evaluation of symptom profile amongst CNDCs with satisfactory internal and external validity. It demonstrates how physical symptoms impact both physical and psychosocial HRQOL, and the cumulative effect of individual symptoms on the overall HRQOL. As such, CNDCs should be systematically screened for multi-systemic symptoms as a routine part of their clinical care, and care plans should be individually catered to individual patients' symptom burden and specific needs.

High FGF-21 level in a cohort of 22 patients with Dravet Syndrome-Possible relationship with the disease outcomes.

OBJECTIVE: Dravet syndrome (DS) is a severe and intractable form of epilepsy with prolonged seizures which may evolve to other seizure types and associated with mild-to-severe intellectual disabilities. Fibroblast growth factor 21 (FGF-21) is a stress hormone mediating metabolic and oxidative stress and circulating level of FGF-21 had been shown to increase in some patients with impairment of oxidative phosphorylation in muscles. In DS, FGF-21 is of interest for further study as mitochondrial oxidative stress was identified previously in patients. METHODS: Plasma FGF-21 levels were compared between 22 DS patients and 22 normal controls, and their clinical characteristics of DS patients at the time of plasma sampling were studied retrospectively. Besides, the relationships of FGF-21 level with intellectual development, seizure frequency, valproate treatment, and types of SCN1A mutations were analyzed. Logarithmic transformation of FGF-21 levels was performed before comparison and statistical analysis. RESULTS: Mean of log10 FGF-21 level was significantly higher in DS patients when comparing with normal controls (P = .0042). Mean of log10 FGF-21 level was significantly higher in DS patients with normal-to-mild ID versus mild-to-severe ID (P = .0193) and with valproate treatment versus without valproate treatment (P = .015). No significant difference was shown in FGF-21 level in DS patients with missense versus truncating SCN1A variants, and no correlation could be demonstrated between seizure frequency and FGF-21 level. SIGNIFICANCE: Significantly higher level of plasma FGF-21 was identified in DS patients. The high FGF-21 levels were shown to be associated with developmental outcome and valproate treatment. These results support further investigation on the relationship of FGF-21 with the clinical outcomes of DS and other related mechanism which is important for possible therapeutic development for this epileptic encephalopathy.

Human d-lactate dehydrogenase deficiency by LDHD mutation in a patient with neurological manifestations and mitochondrial complex IV deficiency.

BACKGROUND: d-lactate, one of the isomers of lactate, exists in a low concentration in healthy individuals and it can be oxidized to pyruvate catalyzed by d-lactate dehydrogenase. Excessive amount of d-lactate causes d-lactate acidosis associated with neurological manifestations. METHODS AND RESULTS: We report here a patient with developmental delay, cerebellar ataxia, and transient hepatomegaly. Enzyme analysis in the patient's skin fibroblast showed decreased mitochondrial complex IV activity. Using whole exome sequencing, we identified compound heterozygous variants in the LDHD gene, which encodes the d-lactate dehydrogenase, consisting of a splice site variant c.469+1dupG and a missense variant c.752C>T, p.(Thr251Met) which are pathogenic and likely pathogenic respectively according to the American College of Medical Genetics and Genomics (ACMG) classification. The serum d-lactate level was subsequently detected to be elevated (0.61 mmol/L, reference value: 0-0.25 mmol/L). CONCLUSION: This is the third report on LDHD mutations associated with d-lactate elevation and was first reported to have decreased mitochondrial complex IV activity. The study provides more information on this rare metabolic condition but the association of LDHD deficiency with the clinical presentations requires further investigations.

Urine organic acid as the first clue towards aromatic L-amino acid decarboxylase (AADC) deficiency in a high prevalence area.

BACKGROUND: Aromatic L-amino acid decarboxylase deficiency is a rare neurometabolic disease due to impaired decarboxylation of neurotransmitter precursors to its active form. CASE: We retrospectively reviewed 8 cases from 2008 to 2019 with cerebrospinal fluid neurotransmitter analysis performed at our centre. All cases had an elevated urine vanillactic acid and, in most cases, with N-acetylvanilalanine detected. Cerebrospinal fluid analysis showed low downstream metabolites vanillylmandelic acid, homovanillic acid but high 3-O-methyl-L-DOPA, 5-hydroxytryptophan. Cerebrospinal fluid pterins were normal. Genotyping in DDC confirms the diagnosis. Urine organic acid analysis provided the first clue to diagnosis in four of the cases, which then triggered cerebrospinal fluid neurotransmitter and genetic analysis. We also developed a diagnostic decision support system to assist the interpretation of the mass spectrometry data from urine organic acids. CONCLUSIONS: Urine organic acid could be essential in guiding subsequent investigations for the diagnosis of aromatic L-amino acid decarboxylase deficiency. We propose to screen suspected cases first with urine organic acids, specifically looking for vanillactic acid and N-acetylvanilalanine. Suggestive findings should be followed with target analysis for c.714 + 4A > T in ethnically Chinese patients. The assistive tool allowed expedite interpretation of profile data generated from urine organic acids analysis. It may also reduce interpreter's bias when peaks of interest are minor peaks in the spectrum.

Exome sequencing in paediatric patients with movement disorders.

BACKGROUND: Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. RESULTS: We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. CONCLUSIONS: A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

White matter integrity in young medication-naïve bipolar II depressed adults.

It is unknown if young medication-naïve bipolar II (BPII) depressed patients have increased white matter (WM) disruptions. 27 each of young (average 23 years) and treatment-naïve BPII depressed, unipolar depressed (UD) patients and age-sex-education matched healthy controls (HC) underwent 3 T MRIs with diffusion tensor imaging. Diagnostic ratings included Structured Clinical Interview for DSM Disorders (SCID), Montgomery-Åsberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS) and Hamilton Anxiety Rating Scale (HAM-A). Patients were clinically depressed (MADRS-BPII: 26.15 [SD9.25], UD: 25.56 [5.24], p = 0.86). Compared to UD, BPII had increased family bipolarity (BPII 13.6% vs UD 2.5%, p = 0.01, φc = 0.28), hypomanic symptoms (YMRS-BPII: 4.22 [4.24], UD: 1.33 [2], p = 0.02, d = 0.87), lifetime number of depressive episodes (BPII: 2.37 [1.23], UD: 1.44 [0.75], p = 0.02, d = 0.91), lifetime and current-year number of episodes (lifetime BPII: 50.85 [95.47], UD: 1.7 [1.03]; current-year BPII: 9.93 [16.29], UD: 1.11 [0.32], ps = 0.04, ds = 0.73-0.77) and longer illness duration (BPII: 4.96 years [3.96], UD: 2.99 [3.33], p = 0.15, d = 0.54). BPII showed no increased WM disruptions vs UD or HC in any of the 15 a priori WM tracts. UD had lower right superior longitudinal fasciculus (SLF) (temporal) axial diffusivity (AD) (1.14 vs 1.17 (BPII), 1.16 (HC); F = 6.93, 95% CI of [Formula: see text]: 0.00073, 5.22, ηp2 = 0.15). Principal component analysis followed by exploratory linear discriminant analysis showed that increased R-SLF (temporal) AD, YMRS and family bipolarity distinguished BPII from UD (81.5% sensitivity, 85.2% specificity) independent of episode number and frequency. Young, medication-naïve adults with BPII depression did not show the WM disruptions distinguishing more chronically ill BP patients from UD. These WM disruptions may therefore be partly attributable to illness chronicity. Longitudinal studies should examine the trajectory of WM changes in BPII and UD and predictive validity of these baseline clinical and imaging parameters.

The KLHL40 c.1516A>C is a Chinese-specific founder mutation causing nemaline myopathy 8: Report of six patients with pre- and postnatal phenotypes.

BACKGROUND: Autosomal recessive or compound heterozygous mutations in KLHL40 cause nemaline myopathy 8, which is one of the most severe forms of nemaline myopathy. The KLHL40 c.1516A>C variant has recently been reported as a founder mutation in southern Chinese. METHODS: We report six cases of nemaline myopathy 8 which involves the c.1516A>C variant, from five unrelated families of non-consanguineous southern Chinese. The pre- and postnatal phenotypes of these cases were reviewed with emphasis on prenatal clinical features. Genetic testing for the founder mutation was performed on three patients with homozygous mutations. RESULTS: Common prenatal features included reduced fetal movement, polyhydramnios, breech presentation, and clubfeet. Two pregnancies were terminated. Four live-born patients had postnatal features typical of nemaline myopathy 8. The length of survival ranged from 49 days to 17 months, with respiratory failure and infections being the principal causes of death. Haplotype analysis in three patients with homozygous mutation showed a shared haplotype block of 1.1727 cM spanning over the c.1516A>C variant, suggesting it is a southern Chinese-specific founder mutation. CONCLUSION: Analysis of the KLHL40 c.1516A>C variant should be considered in prenatal diagnosis of Chinese pregnant patients with suspected congenital neuromuscular disorders or with significant family history of congenital myopathies.

Diagnostic Outcomes of Childhood ADHD in Chinese Adults.

Objective: We examined adulthood diagnostic, functioning, and social outcomes of childhood ADHD in a Hong Kong Chinese clinical sample. Method: We identified from the central registry 499 Chinese adults clinically diagnosed with ADHD aged 6 to 12 in 2002-2005 in four Hong Kong child psychiatric centers. Assessments included ADHD Clinical Diagnostic Scale (ACDS), Structured Clinical Interview for DSM Disorders (SCID), and World Health Organization Disability Assessment Schedule (WHO-DAS). Results: Eligible participants = 499. One hundred forty-five completed assessments, two deceased, six incarcerated, 100 had invalid contact, 83 declined, 34 emigrated, and 129 unable to attend. Mean follow-up duration = 14.9 years. Nonrespondents were slightly younger (19.78 vs. 20.53, p < .001). In all, 83.1% of all participants currently met Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) ADHD criteria (36.8% inattentive subtype (IA), 43% combined, 3.3% hyperactive/impulsive subtype (H/I) ). One third of persistent ADHD participants currently received care. ADHD persistence was associated with significantly increased psychiatric comorbidity (49.5% vs. 22.7%, p = .02) and poor academic and social outcomes. ADHD persistence and comorbidity independently predicted impairment. Conclusion: Adulthood-persistence of clinically presented childhood ADHD is common and impairing in Hong Kong Chinese.

Anti-N-methyl-d-aspartate receptor encephalitis in children: Incidence and experience in Hong Kong.

AIM: The study aims to analyze the incidence, clinical features, investigation findings and treatment outcomes of anti-N-methyl-d-aspartate receptor encephalitis in children from Hong Kong. METHOD: A retrospective study was carried out on paediatric patients diagnosed with anti-NMDAR encephalitis in Hong Kong from January 2009 to December 2015. RESULTS: Fifteen patients (67% female, 93% Chinese) were identified over seven years and the estimated incidence in Hong Kong was 2.2/million children per year (95% CI 1.2-3.6). The median age of presentation was 12 years (range 1-17 years). The most common symptom groups observed were abnormal psychiatric behavior or cognitive dysfunction (14/15, 93%) and seizures (14/15, 93%), followed by speech dysfunction (13/15, 87%), movement disorders (12/15, 80%), decreased level of consciousness (10/15, 67%) and autonomic dysfunction or central hypoventilation (5/15, 33%). The median number of symptom groups developed in each patient was 5 (range 3-6). All patients were treated with intravenous immunoglobulin and/or steroids. Three patients (20%) with more severe presentation required additional plasmapheresis and rituximab. Outcome was assessable in 14 patients. Among those eleven patients who had only received intravenous immunoglobulin and/or steroids, nine patients (82%) achieved full recovery. One patient (9%) had residual behavioral problem, while another one (9%) who developed anti-NMDAR encephalitis after herpes simplex virus encephalitis was complicated with dyskinetic cerebral palsy and epilepsy. Among those three patients who required plasmapheresis and rituximab, one (33%) had full recovery and two (66%) had substantial recovery. The median duration of follow up was 20.5 months (range 3-84 months). CONCLUSION: Anti-NMDAR encephalitis is an acquired, severe, but potentially treatable disorder. Ethnicity may play a role in the incidence of anti-NMDAR encephalitis and we have provided a local incidence with the majority of patients being Chinese. The diagnosis of anti-NMDAR encephalitis should be considered in children presenting with a constellation of symptoms including psychiatric and neurological manifestations. Patients may respond to first line immunotherapy. For those who do not, second line therapy is indicated in order to achieve a better outcome.

Cognitive Impairment In Treatment-Naïve Bipolar II and Unipolar Depression.

Cognition dysfunction may reflect trait characteristics of bipolarity but cognitive effects of medications have confounded previous comparisons of cognitive function between bipolar II and unipolar depression, which are distinct clinical disorders with some overlaps. Therefore, we examined the executive function (WCST), attention, cognitive speed (TMT-A) and memory (CAVLT, WMS-Visual reproduction) of 20 treatment-naïve bipolar II patients (BPII), 35 treatment-naïve unipolar depressed (UD) patients, and 35 age/sex/education matched healthy controls. The subjects were young (aged 18-35), and had no history of psychosis or substance use, currently depressed and meeting either RDC criteria for Bipolar II Disorder or DSM-IV-TR criteria for Major Depressive Disorder. The patients were moderately depressed (MADRS) and anxious(HAM-A), on average within 3.44 years of illness onset. Sociodemographic data and IQ were similar between the groups. UD patients had significantly slower cognitive speed and cognitive flexibility (WCST perseverative error). BPII depressed patients showed relatively intact cognitive function. Verbal memory (CAVLT List A total) correlated with illness chronicity only in BPII depression, but not UD. In conclusion, young and treatment-naïve BPII depressed patients differed from unipolar depression by a relatively intact cognitive profile and a chronicity-cognitive correlation that suggested a stronger resemblance to Bipolar I Disorder than Unipolar Depression.

Radboud Centre for Mitochondrial Medicine Pediatric MRI score.

We developed the first user-friendly, semi-quantitative, and quick-to-perform Radboud Centre for Mitochondrial Medicine Pediatric MRI score (RCMM-PMRIS), focusing on the six most commonly described neuroimaging abnormalities in the literature. The RCMM-PMRIS was validated through individual review of 30 sets of brain MRI studies in 24 patients with genetically confirmed mitochondrial disorders by six raters. The application of RCMM-PMRIS can help to define the extent of the brain involvement and therefore to assess the radiological mitochondrial disease severity, to monitor disease progression and consequently to act as an outcome measure for treatment effects in patients with mitochondrial disease.

Vanishing white matter disease: the first reported chinese patient.

Vanishing white matter disease is a rare neurological disease. The majority of patients reported are Caucasian individuals. We describe the first Chinese patient with typical clinical and radiological features genetically confirmed to have vanishing white matter disease for a mutation in EIF2B4, followed by a brief review of the disease.

Functional Independence Measure for Children: a comparison of Chinese and Japanese children.

OBJECTIVE: The Functional Independence Measure for Children (WeeFIM) is a simple-to-administer scale for assessing functional independence across 3 domains (self-care, mobility, cognition) in children. There are normative data from America and Japan. In 2001 to 2002, the authors created a normative Chinese WeeFIM profile and compared this with the American one. In this study, they aimed to compare their Chinese normative data with the Japanese one. METHODS: A random sampling of 445 normal Chinese children from different social classes in Hong Kong was conducted in the community. It was conducted via face-to-face interviews with the mother, and a normative database was created. RESULTS: Similar to the Japanese children, the WeeFIM total score and 3 main domain subscores (self-care, mobility, and cognition) increased progressively with age. In the self-care domain, Chinese children achieved modified independence or level 6 earlier in all items except toileting. For the mobility domain, the item chair transfer was achieved earlier in the Chinese children, whereas toilet transfer, stair, tub transfer, and locomotion were achieved later in Chinese children. As for cognition domain, the item problem solving was achieved earlier but comprehension, social interaction, and memory were achieved later in the Chinese children. The authors' results showed the same pattern of increasing WeeFIM score with increasing chronological age, which is similar to the Japanese children. There are 3 patterns of WeeFIM score achievement in this Chinese cohort. As for the Japanese children, the 3 patterns of WeeFIM score achievement from independent to dependent are 1) rapid change, 2) gradual change, and 3) linear change. CONCLUSIONS: WeeFIM is a validated standardized tool for assessing the outcome of rehabilitation programs. It should be widely used to assess rehabilitative achievement in children from different ethnic origins. The authors' previous study and this current study demonstrated that the authors' normative WeeFIM profile showed similar results to the American and Japanese children. However, there are minor differences in the WeeFIM scoring in the 3 main domains, which might be due to cultural differences between ethnic groups. Thus, usage of the WeeFIM with a different age criteria in achieving independence according to local culture should be adopted.

Use of chopsticks in Chinese children.

OBJECTIVE: There has been no study on the developmental stage of acquiring the skill of using chopsticks, which is a common eating tool of the Orientals. We aimed to obtain a developmental profile for achieving the skills of chopsticks manipulation in Chinese children and to assess the correlation between chopsticks manipulation and the level of achieving independence in 'eating' item in the Functional Independence Measure of children (WeeFIM). We also studied the relationship between demographic and environmental factors and the age of achieving chopstick manipulation. METHODS: Direct interview with the mothers of 445 non-disabled children who were randomly selected from the community. A chopsticks score (CS) of 1 was defined as children who could use chopsticks to finish more than half the meal, and a CS of 0 as failure to do so. RESULTS: The mean age of achieving a CS of 1 was 4.6 years. At 6.7 years, all these children achieved this skill. There was a significant relationship between age of achieving the skills of chopsticks and the level of attaining independence in 'WeeFIM eating' score. (P < 0.001) However, there was no correlation of age of achieving CS of 1 with sex, social class or the presence of a domestic helper. CONCLUSION: Most non-disabled Chinese children can achieve the visual motor skill of using chopsticks at 4.6 years. There was also a correlation with the age of achieving independence in the WeeFIM eating score. The skill of using chopsticks should be added as part of the tools, apart from spoons or forks, for scoring WeeFIM in Chinese children.

Functional Independence Measure (WeeFIM) for Chinese children: Hong Kong Cohort.

BACKGROUND: The Functional Independence Measure (WeeFIM) for children is a simple-to-administer scale for assessing independence across 3 domains in American children. WeeFIM was based on a conceptual framework by the World Health Organization (1980) of pathology, impairment, disability and handicap, and the "burden of care." WeeFIM is useful in assessing functional independence in children aged 6 months to 7 years. It can be used for children with developmental disabilities aged 6 months to 21 years. Normative WeeFIM data had been validated for American children. Because of cultural and environmental differences among countries, normative data for the Chinese population are needed. With a normative database, the progression of independence at home and in the community can be evaluated. WeeFIM is an 18-item, 7-level ordinal scale instrument that measures a child's consistent performance in essential daily functional skills. Three main domains (self-care, mobility, and cognition) are assessed by interviewing or by observing a child's performance of a task to criterion standards. WeeFIM is categorized into 2 main functional streams: "Dependent" (ie, requires helper: scores 1-5) and "Independent" (ie, requires no helper: scores 6-7). Scores 1 (total assistance) and 2 (maximal assistance) belonged to the "Complete Dependence" category. Scores 3 (moderate assistance), 4 (minimal contact assistance), and 5 (supervision or set-up) belonged to the "Modified Dependence" category. Scores 6 (modified independence) and 7 (complete independence) belonged to the "Independent" category. The WeeFIM is a 7-level criterion-specific ordinal scale. Level 7 requires no assistance for the child and the child completes the task independently without requiring a device. During the task, there is no concern about safety or taking an inordinate amount of time. Level 6 reflects modified independence and includes use of an assistive device or not completing the task in a timely or safe manner. OBJECTIVE: To examine the utility of the WeeFIM in Chinese children and to create a normative WeeFIM profile suitable for Chinese children. METHOD: Direct interviews were conducted for 445 normal Chinese children, aged 6 months to 7 years, in the community. RESULTS: 1. WeeFIM total score and 3 domains subscores versus age. The total WeeFIM scores increased progressively with age, reaching a plateau at 72 months. There was a progressive increase in subscores of self-care, mobility, and cognition independence between 6 to 62 months, especially between 6 to 45 months. Similarly, the WeeFIM self-care subscores increased progressively with age, reaching a plateau at around 72 months. The WeeFIM mobility subscores increased progressively with age, reaching a plateau at around 54 months. The WeeFIM cognition subscores increased progressively with age, reaching a later plateau at around 80 months. 2. WeeFIM subtotal scores versus age. The total WeeFIM score and 3 domain subscores correlated significantly with age. We further classified the 18 items into 3 groups according to the degree of correlation with age. Most items had high correlation with Spearman's correlation coefficient of rho >0.8. Only 1 item (chair transfer) showed moderate correlation with rho = 0.7-0.8. The item "walk" had the lowest correlation with rho = 0.6-0.7. 3. Chronological order for achieving different items. The 50th percentile of age in months for achieving level 6 (modified independence) of the 18 items were compared and ranked according to the age of achieving level 6. In creating a developmental scale of achievement of level 6 (modified independence) for all 18 items, the developmental sequence clustered in the following order: chair transfer (order 1) and walk (order 2) were achieved much earlier (at 18 and 24 months, respectively). Thereafter, there was a clustering of 4 items achieved at around 45 months: toilet transfer (order 3), stair (order 4), expression (order 5), and social interaction (order 6). Then, 9 items were achieved at around 54 to 56 months: tub or shower transfer (order 7), eating (order 8), bathing (order 9), bowel management (order 10), dressing of lower body (order 11), comprehension (order 12), dressing of upper body (order 13), bladder management (order 14), and grooming (order 15). At 60 months, the following ranked in order: memory (order 16), problem-solving (order 17), and toileting (order 18). 4. Impact of sex factor. Girls aged 22 to 45 months had higher scores in self-care subscores and cognition subscores. From 63 months onwards, boys had statistically significant higher scores in mobility subscores. Otherwise, there was no statistically significant difference in WeeFIM scores for different age groups. 5. Impact of domestic helpers. There was also significant difference for self-care subscore with the presence of a maid at home. Those children with a maid at home obtained lower self-care subscores. However, the mobility and cognition subscores were not affected. CONCLUSION: We have created a normative functional independence profile for Chinese children by adapting the American-based WeeFIM. There were cultural differences when compared with American children. Interestingly, Chinese children in Hong Kong scored better than their American counterparts in domain 1 (self-care) in all ages. This might be attributable to early attendance in preschool settings where children are taught to tend to their needs. Even for domain 2 (mobility), the higher scores in younger Chinese children in Hong King (<3 years) might be explained by earlier attendance in preschool settings. The American children did catch up after 3 years. As for domain 3 (cognition), the local educational system emphasized reading, writing, memorizing materials, and social interaction. Thus, Chinese children in Hong Kong had better cognition scores until 42 months, when their American counterparts caught up by attending preschool. There are definitely environmental and cultural practices affecting functional independence in both ethnic groups, especially in the upper age range (>4 years) both in America and Hong Kong. Thus, a locally validated WeeFIM instrument should be adopted for Chinese children. Our study demonstrated that WeeFIM could be used as a functional independence measure for Chinese children. Hong Kong has a different cultural background compared with America; thus, usage of WeeFIM with different age criteria for achieving independence should be adopted.